Research Guy Van Camp

Abstract

Pleural mesothelioma (PM) is a rare and highly aggressive tumor linked to asbestos exposure. Due to its non-specific presenting symptoms and the need for tissue biopsies, diagnosis of PM is delayed, negatively impacting prognosis. Moreover, PM treatment remains palliative due to chemo- and immunotherapy resistance. This emphasizes the need for earlier diagnosis and therapy resistance interception. This could improve patients' outcome, quality of life and even enable the possibility for new treatments. Therefore, in this project, I aim to tackle both late diagnosis and therapy resistance. First, I will construct a diagnostic and a predictive biomarker panel based on PM-specific molecular alterations (differentially methylated CpG sites and copy number alterations) that can be detected in liquid biopsies. The diagnostic biomarker panel is currently being validated. Using IMPRESS, our in-house developed detection technique, we will detect these biomarker panels in circulating tumor DNA, enabling rapid and minimally invasive tumor detection. Additionally, employing a multi-omics approach, I will identify molecular changes and dysregulated pathways associated with acquired chemo-immunotherapy resistance, in a unique patient cohort. These potential therapeutic targets can be used in further research on personalized treatments. Consequently, through this project, I aim to facilitate early diagnosis, minimize toxic side effects, and pave the way towards novel treatment options.

Researcher(s)

• Promoter: Op de Beeck Ken
• Co-promoter: Deben Christophe
• Co-promoter: Van Camp Guy
• Fellow: De Meulenaere Nele

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

This SEP subsidy will contribute to a resubmission of the PhotoCan proposal in which the uptake of a new detection platform in existing population-based screening programmes in Europe is the overarching goal. PhotoCan will contribute to the screening and early detection of cancer via the electrochemical detection of cancer (epi)genetic biomarkers. Those biomarkers are increasingly discovered and validated, but the applicability in everyday medical practice requires low-cost, rapid, accurate and sensitive detection devices. To achieve this, the combined use of electrochemical detection with light-triggered sensor technology for the specific and sensitive detection of preselected cancer (epi)genetic biomarkers is proposed. The application of this technology with single and multiplexing capabilities aims to advance and integrate the technology into prototypes demonstrated in a relevant environment both for screening of colorectal cancer (high incidence) and point-of-care testing of pancreatic ductal adenocarcinoma (low incidence). Via the involvement of oncologists, lab technicians, healthcare professionals, citizens (healthy and patients), screening programmes and health policy makers, PhotoCan will address the implementation requirements from the onset, leading to maximal uptake in existing population-based screening programmes, the creation of new EU-wide screening programmes and the creation of risk-based point-of-care early detection strategies for low incidence, deadly cancers. This SEP grant will be used to appoint a scientist to 1) establish a stronger network with more partners from different EU countries, characterized by different uptake numbers in population-based screening programmes, 2) perform experiments to detect cancer (epi)genetic biomarkers to have a stronger case inviting stakeholders in the field (screening programmes) and 3) coordinate the huge efforts to come to a resubmission, also addressing the feedback from the previous submission.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy

Research team(s)

• Antwerp engineering, PhotoElectroChemistry & Sensing (A-PECS)

Project type(s)

• Research Project

Abstract

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. SOCan will contribute to the (early) diagnosis and follow up of cancer via a new disruptive detection platform, i.e. singlet oxygen-based photoelectrochemical detection of cancer biomarkers. Those biomarkers are increasingly discovered and validated, but the detection necessitates rapid, accurate and sensitive devices. To achieve this, the combined use of electrochemical detection with light-triggered sensor technology for the specific and sensitive detection of pre-selected DNA and RNA cancer biomarkers is proposed. The application of this technology on tissue and liquid biopsy samples will be a major contribution to the early detection of cancer. SOCan aligns with the EU Mission on Cancer and will lead to an affordable and sensitive diagnosis of cancer, reducing the time to result which allows faster and specific treatment, and thereby saving lives.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Cervical cancer is a major impact on public health, causing approximately 150 deaths in Belgium each year. Despite that there is a screening program in Flanders, 37% of the population eligible for cervical cancer screening is not reached by the current program that is based on analysing cervical smears (pap smears). Here, self-sampling, potentially done at home, could pose an alternative strategy for this hard-to-reach population. Infection with the human papillomavirus (HPV) is the cause of nearly all cervical cancer cases. Consequently, HPV detection is currently implemented as screening test. In case HPV is detected, an additional test (triage) is necessary to avoid overtreatment as the majority of HPV infections are spontaneously cleared and do not result in cervical cancer. For this triage the presence of aberrant cells in the pap smear is assessed. HPV detection performs well on self-samples, however, triage by detecting aberrant cells is not possible in this sample type. We will develop a test in which the detection of HPV and triage can be performed in one step on self-samples (as well as traditional cervical samples). As such we hope to reach more women and disturb less. Indeed, fewer women will need to be referred for follow-up causing less (emotional) distress. Thus, in this project we aim to reach more women in cervical cancer screening and give them a better prediction of their cancer risk.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Keer Severien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Inspired by the mission of the EU commission, this project commits to tackle a major societal challenge, i.e. fighting cancer. A striking target for 2030 has been set by the EU: more than 3 million lives saved, living longer and better, achieve a thorough understanding of cancer, prevent what is preventable, optimize diagnosis and treatment, support the quality of life of all people exposed to cancer, and ensure equitable access to the above across Europe. This project contributes to (early) diagnosis and follow up of the disease. More and more biomarkers are discovered and validated for cancer and the highly precise determination thereof is high on the priority list, necessitating analytical devices that allow rapid and accurate analysis with high sensitivity. Electrochemical biochips are an emerging tool for point-of-care diagnostic systems due to their inherent high sensitivity and cost and time effectiveness. We propose the combined use of electrochemical detection with a light-triggered sensing technology for the specific and selective photoelectrochemical detection of low concentrations of cancer biomarkers (i.e. KRAS mutations), also allowing us to detect a panel of cancer biomarkers. Detection and quantification of the selected target sequences will be performed in tissue and liquid biopsies, to ensure the translation from a lab technology to a device for clinicians and even patients.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Koljenovic Senada
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

• Antwerp engineering, PhotoElectroChemistry & Sensing (A-PECS)

Project type(s)

• Research Project

Abstract

Neuroendocrine neoplasms (NENs) exhibit clinical and biological heterogeneity, making diagnosis extremely challenging. Moreover, NENs tend to progress slowly necessitating long-term follow-up to monitor tumor growth and response to therapy. Current modalities for diagnosis and follow-up of NENs are primarily based on imaging and (repeated) tissue biopsies, but these suffer from several shortcomings which have a direct impact on patients' lives. Over the past few years, liquid biopsies have gained interest as a minimally-invasive way for rapid tumor detection and collection of molecular information of the tumor, with circulating tumor DNA (ctDNA) as one of the most promising new markers. This ctDNA is the fraction of cell-free DNA (cfDNA) released by the tumor, that reflects both the genetic and epigenetic alterations of the tumor. Consequently, this project aims to leverage liquid biopsies to improve diagnostic accuracy in NENs and enable real-time monitoring of NEN patients. For this purpose, NEN-specific molecular alterations namely copy number alterations and differentially methylated CpGs will be identified and selected to enable detection and quantification of ctDNA. Since the gold standard detection methods, shallow whole genome sequencing and methylation arrays, respectively, are unable to detect very low concentrations of ctDNA, two alternative and highly sensitive multiplex assays based on DNA sequencing and photoelectrochemistry, respectively, will be employed.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: De Wael Karolien
• Co-promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Fellow: Mariën Laura

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

37% of the population eligible for cervical cancer screening in Flanders is not reached by the current program. Here, self-sampling could pose an alternative strategy for this hard-to-reach population. Persistent infection with the human papillomavirus (HPV) is the cause of nearly all cervical cancer cases. Consequently, HPV DNA detection is considered the superior screening test to date due to its increased sensitivity as compared to cytology. However, it is associated with a lower clinical specificity as the majority of HPV infections are spontaneously cleared and do not result in clinically relevant disease. Thereby an additional triage step is necessary to prevent over-referral and potentially overtreatment which can be done by cytology. HPV DNA-based screening can already be performed on self-samples, however, this is not the case for cytology. By developing a fully molecular, combined screen and triage approach (one-step) based on HPV DNA detection, quantification, genotyping, and DNA methylation and that can be applied on self-samples (as well as cervical samples), we will provide a solution for the current screen and triage challenges. This will avoid over referral and allow better guided management of women needing treatment, while simultaneously increasing the participation rate. As such, the morbidity and mortality of cervical cancer could be reduced and both the health of the patients as well as the costs for the healthcare system would be positively affected.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Keer Severien
• Fellow: van den Borst Eef

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

High-throughput bio-analytical instruments generate an immense data flow. Translating these data into interpretable insights about the underlying processes of life and disease is increasingly dependent on bioinformatics techniques. Since 2012 BIOMINA (biomedical informatics network Antwerpen) brings together bioinformatics expertise, scattered over life science and computer science labs in our university, in an informal network. With this proposal we wish to transform this network, with its expertise and widely used infrastructure, into a BIOMINA core facility that can deliver a professional bioinformatics service. The mission is to 1) build a sustainable support, training, and collaboration model; 2) increase bioinformatics capacity to meet growing demands; and 3) build a strong bioinformatics community. It is proposed by complementary PIs in the field, to translate the available bioinformatics strengths to support biomedical, clinical, biological, and bioengineering labs within the University and external clients in hospitals and industry.

Researcher(s)

• Promoter: Laukens Kris
• Co-promoter: Mateiu Ligia Monica
• Co-promoter: Svardal Hannes
• Co-promoter: Van Camp Guy
• Co-promoter: Van Laere Steven

Research team(s)

• ADReM Data Lab (ADReM)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) represents the third most common cancer type and second leading cause of cancer mortality worldwide. First-line standard treatment in metastatic CRC (mCRC) involves anti-EGFR therapy, which significantly improves progression-free survival (PFS) and overall survival (OS) in RAS/BRAF wild type patients. However, in this group of wild type patients, the response rate is only 30-50%. This indicates that additional resistance mechanisms exist that need to be discovered. Detection of resistance by conventional methods has several limitations. Therefore, there is a need for new, sensitive and specific biomarkers for mCRC management. Preliminary data have shown that methylated DNA biomarkers are promising in CRC detection and follow-up. in this project, I aim to identify differential methylation signatures that can predict primary anti-EGFR response and detect acquired resistance earlier than CT imaging. I will develop two multiplexed assays using droplet digital PCR. One assay will comprise primary resistance biomarkers, with the aim to develop a prediction test on tissue. Another assay will be developed for blood, where the acquired resistance biomarkers will be deployed as follow-up biomarkers allowing real-time monitoring of patients receiving anti-EGFR therapy. The overall aim is to improve the response prediction of these patients and bring us a step closer to personalized medicine.

Researcher(s)

• Promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: de Abreu Ana Regina

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is mostly diagnosed in an advanced incurable stage and therefore, there is a need for new sensitive early detection biomarkers. DNA methylation is a promising field for biomarker detection and we are developing a novel technology that can detect tumour specific methylation signatures in a cost-effective manner. Exhaled breath condensates (EBCs) are an interesting novel source of liquid biopsies in MPM, next to classic blood plasma. We have exciting preliminary data showing that EBCs contain DNA fragments representing full genomes which may lead to a first truly non-invasive MPM detection test. We have preliminary data that an MPM specific methylation signature exists and that our new technology for detecting it works. We will further develop and optimise this new technology and validate it in tissue as well as in liquid biopsies such as blood and EBCs.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Precision medicine is an approach to tailor healthcare individually, on the basis of the genes, lifestyle and environment of an individual. It is based on technologies that allow clinicians to predict more accurately which treatment and prevention strategies for a given disease will work in which group of affected individuals. Key drivers for precision medicine are advances in technology, such as the next generation sequencing technology in genomics, the increasing availability of health data and the growth of data sciences and artificial intelligence. In these domains, 6 strong research teams of the UAntwerpen are now joining forces to translate their research and offer a technology platform for precision medicine (PreMeT) towards industry, hospitals, research institutes and society. The mission of PreMeT is to enable precision medicine through an integrated approach of genomics and big data analysis.

Researcher(s)

• Promoter: Laukens Kris
• Co-promoter: Bittremieux Wout
• Co-promoter: Kooy Frank
• Co-promoter: Loeys Bart
• Co-promoter: Meester Josephina
• Co-promoter: Meysman Pieter
• Co-promoter: Mortier Geert
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim
• Co-promoter: Verstraeten Aline
• Fellow: Bosschaerts Tom
• Fellow: Gauglitz Julia

Research team(s)

• ADReM Data Lab (ADReM)

Project type(s)

• Research Project

Abstract

GENOMED is an interfaculty consortium of four research groups and Center of Excellence at the University of Antwerp. The general aim of GENOMED is to enhance genetic research in biomedical sciences by application of state-of-the-art technologies such as next generation sequencing (NGS), induced pluripotent stem cells (iPSC) and gene editing (CRISPR/Cas). In the past few years, GENOMED has focused on exome sequencing which has led to new gene discoveries but now anticipates that whole genome sequencing (WGS) will become the next standard genetic analysis and an essential step towards personalized medicine. The future research within GENOMED will focus on two major challenges: first, the development of technologies that allow better understanding of the biological meaning of both coding and noncoding genetic variants in the human genome, and second, the translation of these new genetic findings into better diagnostics and treatment. At present, the major bottleneck with NGS is the ability to distinguish causal mutations from benign variants. The study of the functional effect of these variants will be key in the understanding of the disease biology but also necessary for the translation into personalized medicine. It will require robust and efficient systems to explore the functional consequences of these variants by using in vitro cell cultures (especially iPSC) and/or animal models (mouse, zebrafish) that are representative for the human disorder. To address the second challenge, the consortium will establish collaborations with clinicians and industry to transfer genetic knowledge into biomarkers and to translate the new genetic insights into innovative therapies.

Researcher(s)

• Promoter: Loeys Bart
• Promoter: Mortier Geert
• Co-promoter: Kooy Frank
• Co-promoter: Loeys Bart
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Inspired by the mission of the EU commission, this project commits to tackle a major societal challenge, i.e. fighting cancer. A striking target for 2030 has been set by the EU: more than 3 million lives saved, living longer and better, achieve a thorough understanding of cancer, prevent what is preventable, optimise diagnosis and treatment, support the quality of life of all people exposed to cancer, and ensure equitable access to the above across Europe. This project contributes to (early) diagnosis and follow up of the disease. More and more biomarkers are discovered and validated for cancer and the highly precise determination thereof is high on the priority list, necessitating analytical devices that allow rapid and accurate analysis with high sensitivity. Electrochemical biochips are an emerging tool for point-of-care diagnostic systems due to their inherent high sensitivity and cost and time effectiveness. We propose the combined use of electrochemical detection with a light-triggered sensing technology for the specific and selective photoelectrochemical detection of low concentrations of cancer biomarkers (i.e. KRAS mutations). In this project we will focus on the development of a multiplexed 96-well plate-based detection of a panel of cancer biomarkers. Detection and quantification of the selected target sequences will be performed in liquid biopsies, to ensure the translation from a lab technology to a device for clinicians and even patients.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Koljenovic Senada
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Inspired by the mission of the EU commission, this project commits to tackle a major societal challenge, i.e. fighting cancer. A striking target for 2030 has been set by the EU: more than 3 million lives saved, living longer and better, achieve a thorough understanding of cancer, prevent what is preventable, optimize diagnosis and treatment, support the quality of life of all people exposed to cancer, and ensure equitable access to the above across Europe. This project contributes to (early) diagnosis and follow up of the disease. More and more biomarkers are discovered and validated for cancer and the highly precise determination thereof is high on the priority list, necessitating analytical devices that allow rapid and accurate analysis with high sensitivity. Electrochemical biochips are an emerging tool for point-of-care diagnostic systems due to their inherent high sensitivity and cost and time effectiveness. We propose the combined use of electrochemical detection with a light-triggered sensing technology for the specific and selective photoelectrochemical detection of low concentrations of cancer biomarkers (i.e. KRAS mutations), also allowing us to detect a panel of cancer biomarkers. Detection and quantification of the selected target sequences will be performed in liquid biopsies, to ensure the translation from a lab technology to a device for clinicians and even patients.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) and breast cancer are amongst the most common and deadliest cancers worldwide. Early detection through current screening programs for both cancers have reduced mortality, but important limitations of these methods, such as limited sensitivity, limited specificity and invasiveness, remain. There is a need for a new, minimally-invasive, cost-effective and very sensitive diagnostic test for screening and early cancer detection. Methylated circulating tumor DNA (metctDNA) biomarkers have shown great potential to discriminate between normal tissue and tumors. MetctDNA can be detected in a minimally-invasive manner using liquid biopsies, such as plasma. Currently, DNA methylation is studied using bisulfite conversion followed by next-generation sequencing or droplet digital PCR. However, disadvantages including DNA degradation, non-optimal sensitivity and specificity of subsequent techniques and limited multiplex capacities still need to be overcome. At this moment, there exists no efficient technique for the simultaneous analysis of several methylated regions in ctDNA in one assay. In our research group, we aim to develop a new, sensitive multi-region metctDNA based bisulfite-free detection technique. The technique will be used in this project to detect differential methylation signatures between normal tissue, pre-cancerous lesions and tumors. With this approach, we aim to develop a new and better assay for screening and detection of CRC and breast cancer.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Co-promoter: Van Hal Guido
• Fellow: Neefs Isabelle

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Many advances in systemic therapies have significantly improved the survival of patients with metastatic colorectal cancer (mCRC). However, there is a high variability of therapeutic responses among patients and determining the optimal personalized treatment plan is challenging. Conventional monitoring of the therapy response is based on imaging as suggested in RECIST 1.1 and measurements of tumormarkers (e.g. CEA) derived from plasma. However, radiological assessments are usually limited in frequency (radiation exposure, costs, logistics,…), have a detection limit, are not suited for small metastases and cannot describe intrinsic characteristics of each tumor. Therefore, other predictive biomarkers of treatment outcomes and disease progression are of great value to enable early therapy response evaluation and early change of therapy avoiding unnecessary side effects, enhancing efficacy and minimizing costs. Quantification of ctDNA in real-time renders information on tumor characteristics and has been shown to be associated with treatment responses in mCRC. Recently, our research group has shown that quantifying ctDNA through the methylation analysis of NPY in circulating DNA is a good marker for total tumor burden and can therefore be used for the follow-up of mCRC patients. It could be demonstrated that the amount of circulating tumor DNA (ctDNA) in plasma, measured using NPY ddPCR methylation assays, decreased immediately (14 days) after treatment start. The amount of ctDNA remained low or undetectable in patients undergoing curative metastasectomy, while the amount of ctDNA increased in patients showing progressive disease. As progressive disease might be detected earlier using liquid biopsies as compared to observations by radiographic evaluation, the use of liquid biopsies might be a promising tool to guide treatment options. The aim of this study is to determine the optimal cutoff value of the liquid biopsy test (using a ROC curve based on the data of this study). This cutoff value will be used in a follow-up study to detect progressive disease in patients with metastatic colorectal cancer treated with first-line FOLFOX/FOLFIRI and panitumumab. Additionally, the follow-up trial will determine if ctDNA detects progression earlier than conventional used imaging techniques and will estimate the effect on progression-free survival in case therapy is guided by NPY methylation levels in liquid biopsy. Furthermore, in the LEAD-IN FOLICOLOR Trial we will exploratively compare liquid biopsies to tumor markers (CEA and/or CA19.9) in their ability to predict progressive disease. This innovative study will add evidence to the clinical relevance of ctDNA during treatment.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Each year, an estimated 8.2 million people die of cancer. With appropriate detection methods and treatment, many of these deaths would be avoidable. Due to the high incidence and mortality rates, early and accurate diagnosis is paramount for a quick and adequate treatment of patients. Until recently, no truly non-invasive diagnostic methods for the detection of cancer existed. An attractive novel method is the detection of abnormally expressed biological markers manifested during carcinogenesis in so called "liquid biopsies". Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or peripheral blood, are sampled and analysed for disease diagnosis. The analysis of Circulating tumor DNA (CtDNA) in cancer patients is not new and has been performed in the past. However, until now, a strong focus existed on the detection of tumor specific mutations, which has several limitations. The use of methylation markers instead of mutation markers has many advantages and is understudied. We have recently published GSDME as a highly sensitive and specific methylation biomarker for both breast and colorectal cancer. We wish to build upon these data and extend our search for suitable cancer detection biomarkers genome wide. One of the problems with liquid biopsy nucleic acid biomarkers is the limited sensitivity for early detection. Indeed, in early stages of carcinogenesis, many tumor types have low concentrations of CtDNA. Sensitivity can be increased by measuring a multitude of markers simultaneously. However, to date, no efficient techniques exist that allow multi-region methylation analysis in plasma. Therefore, in this project, we will design a novel technique, next generation high resolution methylation detection in plasma of cancer patients and develop a novel multi-region pan-cancer detection assay, based on genome wide methylation tumor data. We believe that this novel technology is able to increase sensitivity 100 - 1000 fold while reducing the cost more than a 100 fold compared to the standard technologies that are used nowadays. Finally, we will validate our novel technique and assay in clinical samples.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Fransen Erik
• Co-promoter: Peeters Marc

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Each year, an estimated 8.2 million people die of cancer. With appropriate detection methods and treatment, many of these deaths would be avoidable. However, current methods for detection and analysis of treatment response still suffer from major disadvantages. An attractive novel method is the detection of abnormally expressed biological markers manifested during carcinogenesis in so called "liquid biopsies". Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or peripheral blood, are sampled and analysed for disease diagnosis. The analysis of CtDNA (DNA originating from the tumor and present in the blood) in cancer patients is not new and has been performed in the past. However, until now, a strong focus existed on the detection of tumor specific mutations, which has several limitations, such as limited sensitivity. The use of methylation markers instead of mutation markers has many advantages, such as a potentially much higher sensitivity, and is understudied. We have recently published GSDME as a highly sensitive and specific methylation biomarker for both breast and colorectal cancer. In addition, we have analyzed 12 additional frequent cancer types, and we have strong preliminary data that GSDME is about equally sensitive in each of these 14 tumor types analyzed. These data show that GSDME has strong potential as the first true pan-cancer biomarker. In part A of the project, we will focus on GSDME, and test it as a true biomarker in a clinical setting. Next to detection markers, there is also a need for better follow-up markers. Follow-up of cancer patients is currently performed based on clinical, radiologic and tumor marker evaluation, which has limitations. Better follow-up markers have the potential to detect resistance or disease progression earlier. We aim to expand further on these concepts and conduct a clinical trial where we will evaluate the use of GSDME methylation analysis in liquid biopsies as a tool to guide treatment in metastatic colorectal patients and to explore whether GSDME has potential as a follow up biomarker (WP2). Moreover, GSDME has an interesting physiological function. Recent papers have identified Gasdermins, including GSDME, as a completely new type of regulated cell death executioners (RCD). Recently, it was proven that the N-terminal part of GSDME induces RCD through pore-formation and this is a key antitumor mechanism that is inactivated in several tumor types. In a third work package of part A, we will further investigate these fundamental aspects of the GSDME gene and study its involvement in carcinogenesis. One of the problems with liquid biopsy nucleic acid biomarkers is the limited sensitivity for early detection. Indeed, in early stages of carcinogenesis, many tumor types have low concentrations of CtDNA. Sensitivity can be increased by measuring a multitude of markers simultaneously. However, to date, no efficient techniques exist that allow multi-region methylation analysis in plasma. Therefore, in part B of this project, we will design a novel technique that is able to do this. In a previous unpublished analysis, we have shown that the cancer methylome contains a multitude of differentially methylated makers, that hold the potential to be used as pan-cancer biomarkers, and we have developed a bioinformatics analysis pipeline to detect and rank these according to their discriminating power. Using these data, we will develop a novel multi-region pan-cancer detection assay using our novel technique. We believe that our technology is able to increase sensitivity 100 - 1000 fold while reducing the cost more than a 100 fold compared to the standard technologies that are currently used for CtDNA biomarkers. Finally, we will validate our novel pan-cancer detection assay in the clinical samples that were collected in part A.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Fransen Erik
• Co-promoter: Peeters Marc

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Lung cancer is a heterogeneous disease with high prevalence and mortality. Despite improvements in treatment, lung cancer takes over 1,000 lives each day in Europe alone. The benefit of targeted therapy is illustrated for ALK-driven non-small cell lung cancer (NSCLC), with a median survival of 7 years, compared to <20% overall 5 year survival for lung cancer in general. As targeted inhibitors do not actively kill tumor cells, aberrant cells remain dormant in the patient. To tackle inevitable resistance and disease progression, novel generation drugs are needed to target the resistance mechanism. However, for ROS1-fusions, a relatively recently described oncogene representing 1-2% of NSCLC, only a single targeted drug is currently approved. Hence, patients resort to chemotherapy, off-label use or clinical studies on disease progression. Due to the scarcity of ROS1+ NSCLC, clinical decisions are guided by sporadic case reports and in vitro experiments based on synthetic setups in non-human cell models. Here, we couple modern genome engineering and computational prediction on drug/target interactions with patient-driven efforts to generate relevant disease models. We will introduce 13 known and predicted resistance mutations into 6 patient-derived cell lines, followed by experimental and computational evaluation of available targeted drugs. Complementing experimental and computational data results in an objective model to guide clinical decision making in rare cancer types.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Pauwels Patrick
• Co-promoter: Vandeweyer Geert

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. At current, it is believed that the presence of aberrant COCH proteins in the extracellular matrix (ECM) of the inner ear leads to local cell damage resulting in progressive hearing loss. Within Belgium and the Netherlands, there are > 1000 patients affected by the P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness and balance loss. Furthermore, there are over twenty different COCH mutations identified in people from all over the world that lead to SNHL. Given the genetic nature of this disorder with highly specific mutations, as well as recent advances in CRISPR-nuclease mediated gene therapeutic approaches, there is a great opportunity to develop a successful therapeutic strategy to reduce or prevent DFNA9-induced SNHL.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Camp Guy

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

With an estimated 8.8 million deaths yearly, the cancer burden weighs heavily on populations globally. Early detection of cancer is one of the key aspects that results in improved patient prognosis. In this respect, the analysis of circulating tumor DNA in plasma is potentially a major enhancement over currently used imaging, immunochemincal or histopathological methods. Highly sensitive and specific biomarkers for the most common types of cancer are currently still lacking however. In light of recent publications, DNA methylation holds great promise as a tumour marker, but it is yet to be fully explored in the context of liquid biopsies. Our preliminary data shows that CpG methylation can be used to effectively detect cancer and determine different tumors. Our research group is developing a new, robust, and cost-effective diagnostic assay using methylation markers, termed MeD-smMIPs-seq. This assay will combine methylated DNA sequencing with single molecule molecular inversion probes to target highly informative CpGs and achieve high diagnostic sensitivity while reducing assay costs. The aim of this project is first to identify the most informative differentially methylated regions genome-wide, that can be used as cancer biomarkers in this assay. Secondly, we aim to develop the bioinformatics framework required for new experimental design and downstream data analysis. Finally, we will validate the assay and the computational pipeline in the context of liquid biopsies.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Peeters Marc
• Fellow: Ibrahim Joe

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Early and accurate detection of cancer has great potential to reduce mortality, as treatment is often more successful in early stages. The currently used methods for cancer detection and screening have important limitations such as low sensitivity in early stages and invasiveness. There is a clear need for new minimally invasive, costeffective and sensitive diagnostic tests that are also capable of early cancer detection for all cancer types. Circulating tumor DNA (ctDNA) methylation biomarkers have the potential to be used in such minimally invasive tests for cancer diagnosis. Further studies are however required to improve the insufficient sensitivity and specificity of methylation ctDNA (MetctDNA) based tests. Digital droplet PCR is the golden standard for ctDNA analysis. However, the need for DNA damaging bisulfite conversion and limited targets that can be multiplexed are important disadvantages. Currently no cost effective, efficient and sensitive techniques exists for the analysis of multiple methylation sites in ctDNA. To remediate this, we have obtained in our lab a proof of concept for a sensitive, multi-region MetctDNA based bisulfite-free detection technique. The general aim of this project is to develop this technique into a pan-cancer detection assay. A high sensitivity and pan-cancer performance is expected to be reached by combining 1000 methylation biomarkers with this technique.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Fellow: Van Houte Alena

Research team(s)

Project type(s)

• Research Project

Abstract

Everolimus is a targeted therapy commonly used for patients with advanced pancreatic neuroendocrine tumors (PNETs). Unfortunately, after a while patients develop resistance, seen as progression on medical images. Earlier detection of resistance allows a quicker change to more effective therapies, results in better patient outcome, spares patients from ineffective treatment and reduces costs for society. Building on cell line data, fusion genes will first be studied in everolimus-naïve PNET patients as they may represent interesting genetic markers. For further experiments, tissue and monthly blood and urine samples from 30 PNET patients starting everolimus treatment will be collected (EVEREST trial). To identify the first resistance-predicting mutations, the DNA sequence of tumor tissue before and after everolimus-resistance will be compared. Next, we will study the possibility of detecting predictive mutations in non-invasively obtainable tumor DNA fragments in blood and urine (CtDNA) and of using serial CtDNA level measurements as a follow-up marker, both aiming at earlier detection of everolimus-resistance. CtDNA level is estimated by detection of tumor-specific mutations in serial plasma and urine samples. These mutations should be present at baseline and are selected based on the tumor's genetic profile, the experiment on fusion genes, previously obtained results and literature. We expect to detect a rise in CtDNA level when resistance develops.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: Boons Gitta

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

DNFA9 is a cause of autosomal dominant (AD) non-syndromic late-onset sensorineural hearing loss (SNHL) associated with progressive bilateral vestibular failure (BVF). The age of SNHL onset varies depending on the mutation though the average onset age lies around 3rd-5th decade. It typically starts as downsloping of the audiogram at the age of onset and evolution towards deafness. DFNA9 is caused by mutations in the COCH gene (Coagulation Factor C Homology), which is located on chromosome 14q12-13 and encodes for a 550 amino acid protein, cochlin, which is expressed throughout the inner ear in spindle-shaped cells located along nerve fibers between the spiral ganglion and sensory epithelium. Over twenty mutations have been identified in regions, including North America, Japan, Australia, Korea, China and Belgium/Netherlands. Our objective is to establish an in vitro proof-of-principle for a gene therapeutic approach that targets mutant cochlin expression in the inner ear using Anc80L65AAV/CRISPR/Cas9-mediated gene editing. We hope to establish in vitro that this technique enables specific correction or downregulation of the mutant COCH gene in mammalian cell lines without modulating the normal COCH allele, which is still present in this heterozygous disorder. This work can provide proof-of-concept for in vivo studies in transgenic heterozygous COCH mice targeting the mutated COCH gene by means of an AAV.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Everolimus is a targeted therapy commonly used for patients with advanced pancreatic neuroendocrine tumors (PNETs). Unfortunately, after a while patients develop resistance, seen as progression on medical images. Earlier detection of resistance allows a quicker change to more effective therapies, results in better patient outcome, spares patients from ineffective treatment and reduces costs for society. Building on cell line data, fusion genes will first be studied in everolimus-naïve PNET patients as they may represent interesting genetic markers. For further experiments, tissue and monthly blood and urine samples from 30 PNET patients starting everolimus treatment will be collected (EVEREST trial). To identify the first resistance-predicting mutations, the DNA sequence of tumor tissue before and after everolimus-resistance will be compared. Next, we will study the possibility of detecting predictive mutations in non-invasively obtainable tumor DNA fragments in blood and urine (CtDNA) and of using serial CtDNA level measurements as a follow-up marker, both aiming at earlier detection of everolimus-resistance. CtDNA level is estimated by detection of tumor-specific mutations in serial plasma and urine samples. These mutations should be present at baseline and are selected based on the tumor's genetic profile, the experiment on fusion genes, previously obtained results and literature. We expect to detect a rise in CtDNA level when resistance develops.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: Boons Gitta

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide with a high morbidity and mortality. Although CRC can be cured in most cases when it is detected in its early stages, the treatment of patients with metastatic CRC (mCRC) still has its limitations. Accurate monitoring of tumor disease and appropriate tumor tissue for mutation-analysis before anti-EGFR therapy are lacking. Possible solutions can be found in liquid biopsies. During my PhD, a lot of time and effort has been put in starting up a clinical trial recruiting mCRC patients treated in first-line with targeted therapies. Blood samples are collected at four different time points during treatment for the isolation of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). Our first pilot study on 24 patients has just been finished and reveals exciting results. We find out that it is possible to monitor tumor disease during treatment using mutation and methylation digital droplet PCR (ddPCR) assays on ctDNA and these results were also corresponding with the imaging results. We would like to confirm these results on an expanded study cohort where additional monthly blood samples are collected between time point 3 (first radiographic evaluation) and 4 (disease progression or curative surgery). In this way, we want to investigate whether it is possible to early detect progression, meaning before detection by radiographic evaluation. At this moment, we have the knowledge, the patients (n=40) and the motivation to perform these highly interesting experiments, we only need some extra time. In addition, some additional experiments should be performed on ctDNA of serum samples to make a clear comparison between plasma and serum samples. If our results would indicate that ctDNA isolated from serum samples follows the same trend as plasma samples during tumor disease monitoring, this will be the start of multiple liquid biopsy studies as a lot of serum samples are stored in the biobank of different hospitals. Lastly, we want to finish our study on CTCs. Up to now, we performed already expensive and time-consuming detection and isolation of CTCs. Unfortunately, we did not have the time yet to perform whole genome amplification and mutation detection. It would be very interesting to evaluate whether CTCs reveal the same or additional information compared to circulating DNA. In conclusion, liquid biopsies are promising tools in mCRC treatment. We managed to collect a very interesting patient cohort and showed already some exciting results. Unfortunately, due to lack of time, the majority of the samples has not yet been studied. Thanks to the acquired expertise so far, I believe that we can perform very interesting experiments with a minimal time investment (12 months) which enables me to successfully and proudly finish this PhD.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

There still is a large unmet need to improve the diagnosis, treatment and treatment monitoring of patients suffering from Malignant Pleural Mesothelioma (MPM). In other cancer types, the detection of genomic alterations, resulting in the identification of actionable or prognostic biomarkers, has been proven helpful to improve treatment. Hence, the objectives of this research project are: (i) to gain insight into recurrent, actionable genetic alterations in MPM, which can be useful to monitor disease progression and treatment effectiveness; (ii) to understand the genetic factors involved in resistance to chemotherapy and (iii) to explore the detection of genetic alterations in circulating tumour DNA for its potential in early diagnosis and disease monitoring. To achieve this, a meta-analysis will be performed on in-house and publicly available sequencing data, samples of responding and non-responding patients will be sequenced by whole exome sequencing, and serial blood samples of MPM-patients will be analysed.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: Van Camp Guy

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a frequently used treatment modality in advanced pancreatic neuroendocrine tumors (PNETs), since a placebo-controlled phase III trial demonstrated an increased progression-free survival in the everolimus monotheraphy arm. Somatostatin analogues (SSA), such as octreotide and lanreotide, have been used for over 25 years for symptom control in hormone-secreting PNETs. Additionally, recent studies have demonstrated an anti-proliferative effect in PNETs. Initial phase II studies have shown the feasibility and safety of combining both treatments in patients and both drugs are frequently combined in practice. As both treatment modalities only rarely induce objective response (OR) according to the imaging-based RECIST criteria, follow-up of treatment efficacy remains challenging on imaging, as disease stabilization (SD) is often the treatment target. Measuring circulating tumor DNA (CtDNA), shedding directly from the tumor mass and detectable through a non-invasive blood sample, has been correlated to targeted treatment response in colorectal cancers, but has not yet been studied in PNETs and could be a disease progression marker before it is apparent on imaging. Additionally, no predictive biomarkers currently exist to determine which patients benefit most from combined everolimus and octreotide treatment. In this prospective, multi-center, proof-of-concept clinical trial, 30 patients will receive combination treatment with everolimus and octreotide. Primary outcome will be feasibility of treatment follow-up through CtDNA markers. Tumor-specific mutations will be identified through next-generation sequencing of formalin-fixed paraffin-embedded (FFPE) tumor tissue. These tumor-specific mutations will be quantified in CtDNA using digital-droplet PCR during treatment. Feasibility is defined as detection of an increase of 20% of selected CtDNA markers 2 months before progression, according to RECIST, is apparent on imaging. Secondary endpoints include identification of a predictive biomarker for time to progression using ultra-deep next generation sequencing of FFPE tumor tissue, overall response rates, time to progression and safety of the combination treatment according to the Common Terminology Criteria for Adverse Events 4 (CTC-AE 4).

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This research project focuses on DFNA5 based upon strong indications for its role as tumour suppressor gene, its function in apoptosis and its potential role as early biomarker in cancer. DFNA5 was identified in 1998 in our lab, as a gene causing autosomal dominant non syndromic hearing loss [3]. Since then, a number of papers on DFNA5 have been published pointing towards a possible involvement in cancer [4-15].

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Camp Guy
• Fellow: Croes Lieselot

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer metastases is responsible for 90% of the cancer related deaths. Due to an increased knowledge of the biology of cancer, more patients are referred to targeted therapy. The efficacy of these drugs depends on the molecular characteristics of the cancer cells. In addition, recent research has shown that molecular characteristics of cancer cells can change during cancer progression and metastasis. Since it is practically difficult to sample metastatic tissue repeatedly, investigating alternative matrices is imperative, paving the way for liquid biopsies. One possibility is to evaluate the molecular characteristics of circulating tumor cells, obtained from peripheral blood. However, before these cells can be used as matrix for molecular diagnostics, is should be evaluated if these CTCs have the same characteristics as the primary or metastatic tumor cells. In addition, due to heterogeneity in the primary tumor/metastases, is should be evaluated how many CTCs need to be analyzed in order to capture the dominant driving clones. In order to evaluate this, genomic changes from CTCs will be compared to the genomic composition of the primary tumor and the metastases. If successful, this project will allow a translation of liquid biopsies from the bench to the bedside, sparing patients from difficult and painful treatments.

Researcher(s)

• Promoter: Van Laere Steven
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: Brouwer Aaltje

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Mortier Geert
• Co-promoter: Kooy Frank
• Co-promoter: Loeys Bart
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This research project focuses on DFNA5 based upon strong indications for its role as tumour suppressor gene, its function in apoptosis and its potential role as early biomarker in cancer. DFNA5 was identified in 1998 in our lab, as a gene causing autosomal dominant non syndromic hearing loss [3]. Since then, a number of papers on DFNA5 have been published pointing towards a possible involvement in cancer [4-15].

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Camp Guy
• Fellow: Croes Lieselot

Research team(s)

Project type(s)

• Research Project

Abstract

During this PhD project, we want to gain insights in the pathophysiology of keratoconus (KC). Identification of the disease-causing genes is our primary goal. Afterwards we will investigate the role of these genes in the pathophysiology of KC and the biological processes in which they are involved.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Koppen Carina
• Fellow: Valgaeren Hanne

Research team(s)

Project type(s)

• Research Project

Abstract

Impairment in auditory and/or visual senses has a great impact on a child's ability to learn by affecting their access to the physical, social, and instructional environment. Congenital sensory disorders are often caused by a mutation in a single gene, and can be designated as monogenic disorders. The identification of these genes is one of the main goals of this project and is of significant importance in understanding normal pathological and physiological processes. Previous gene identifications have created a revolution in biology, and the identity of many major molecular players the process of sense were revealed. Classical biochemical and biological methods trying to identify these molecules had yielded limited success before. The genetic identifications lead to major breakthroughs in the understanding of the physiology, through functional studies, animal models, identification of family members and interacting proteins.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Schrauwen Isabelle

Research team(s)

Project type(s)

• Research Project

Abstract

The project aims at supporting the claims of two UAntwerp patents. The technology protected by these patents offer an alternative to "label free detection systems" on the market today, and cover a new platform for fast and accurate detection of selected small molecules.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Blust Ronny
• Co-promoter: Nagels Luc
• Co-promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of the BeMGI project is to establish a vibrant network devoted to medical genomics, including Belgian top scientists active in the field of human genetics, in order to: (i) boost individual research efforts towards understanding the biology of disease by promoting collaborative exploitation of the most advanced genomic tools. (ii) develop approaches to predict clinical outcome from genomic information and fulfil a pilot role towards concerted integration of genomic information in clinical care in Belgium. (iii) play a catalyzing role in preparing the next generation of genomics researchers, informing medical practitioners about evolving trends in medical genomics, and conducting public outreach.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The main focus of project will be on the analysis and replication of the Genome Wide Association Study (GWAS). We also are performing exome sequencing to look for deleterious rare variants.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Fransen Erik
• Fellow: Bonneux Sarah

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Rossom Sofie

Research team(s)

Project type(s)

• Research Project

Abstract

The goal of this project is to identify genetic factors that contribute to the development of otosclerosis. Firstly, we will perform linkage analysis and positional cloning in large families with autosomal dominant otosclerosis. Secondly, we will perform a genome wide association study (GWAS) with individual genotyping in a large set of patients and controls.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Schrauwen Isabelle

Research team(s)

Project type(s)

• Research Project

Abstract

The availability of DNA microarrays, allowing the automated genotyping of 100.000s of single nucleotide polymorphisms (SNPs), has revolutionized human genetics. Genome-wide association studies have begun to uncover the genetic basis of several complex diseases and phenotypes. The aims of this project are: 1) to develop new gene mapping methods that employ dense SNP data, 2) to investigate the genetic structure and evaluate the potential for linkage disequilibrium disease mapping in an isolated population, the Finnish Saami, and 3) to identify genes involved in the etiology of age-related and nonsyndromic hearing impairment.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Huyghe Jeroen

Research team(s)

Project type(s)

• Research Project

Abstract

In human genetic diagnostics, there is a large need for instruments that can detect DNA variants and mutations efficiently and cost-effectively. Current fluorescent methods are expensive and often not suitable for extended multiplex analysis. The aim of this study is the development of a potentiometric coated wire sensor that is able to reliably and quickly detect DNA variants, by adapting a successful sensor platform that has been developed previously at the University of Antwerp.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Nagels Luc

Research team(s)

Project type(s)

• Research Project

Abstract

In this project we propose to unravel the role of DFNA5 in apoptosis and to study its function using a variety of approaches. Firstly, we will study the apoptotic mechanism in a yeast model and identify modulators of the apoptotic phenotype and interacting partners of DFNA5. These genes will be further analysed in mammalian cell lines. We will also construct and study a mouse model expressing mutant DFNA5. As a last objective of the project, we aim to crystallize the DFNA5 protein and determine the three dimensional structure by x-ray diffraction.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut
• Fellow: Op de Beeck Ken

Research team(s)

Project type(s)

• Research Project

Abstract

Although over the last 10 years the identification of genes for monogenic deafness has been very successful, diagnostic applications are lagging behind. The main obstacle for better DNA diagnostics is the high cost of DNA sequencing. In the current project we will develop a novel molecular diagnostics approach targeted to hereditary deafness, with the goal of providing high throughput, sensitive, reliable and cost effective diagnostic tests. We aim to develop reliable DNA diagnostics comprising all 30 known genes for autosomal recessive deafness on a 454 GS-FLX DNA sequencer (Roche). The method will enable us to analyse these deafness genes within a few weeks at an affordable cost. Therefore, a genetic diagnosis should be obtained in a much higher percentage of patients compared to current methods. Multiplex PCR will be performed for all exons of the genes. Specific sets of primers are designed carefully to pool amplicons in the same PCR reaction. Reaction conditions for each of these multiplex PCR reactions will be optimized. After validation, up to sixty different tags are available to distinguish patient's DNA, so batches of up to 60 patients will be sequenced in a single run. After the method has been validated, we will analyse 350 patients using this system. All patients included will have non-syndromic, moderate to profound HL, and unaffected parents from European ethnicity. The results of this analysis will teach us the relative contribution of the different genes to ARNSHL in Europe, data which are currently unavailable, and which are very important for DNA diagnostics.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Age-Related Hearing Impairment (ARHI), the most prevalent sensory impairment in the elderly, is a complex disease caused by environmental and genetic factors. Our laboratory recently identified two susceptibility genes for ARHI, GRHL2 and GRM7. The current project will elaborate the role of these two genes for the development of ARHI by genetic and functional studies.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Bonneux Sarah

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to acquire better insights into the development of ARHI, a complex type of hearing loss. To achieve this we will firstly perform additional investigations on two recently identified ARHI susceptibility genes, GRHL2 and GRM7, using genetic and functional studies.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

The availability of DNA microarrays, allowing the automated genotyping of 100.000s of single nucleotide polymorphisms (SNPs), has revolutionized human genetics. Genome-wide association studies have begun to uncover the genetic basis of several complex diseases and phenotypes. The aims of this project are: 1) to develop new gene mapping methods that employ dense SNP data, 2) to investigate the genetic structure and evaluate the potential for linkage disequilibrium disease mapping in an isolated population, the Finnish Saami, and 3) to identify genes involved in the etiology of age-related and nonsyndromic hearing impairment.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Huyghe Jeroen

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims firstly at identification of genes responsible for monogenic forms of otosclerosis, a form of progressive hearing loss. This will be accomplished by positional cloning using large autosomal dominant families. A second aim is the identification of genetic risk factors for complex forms of otosclerosis by genetic association studies using large patient collections with the complex form of otosclerosis.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Schrauwen Isabelle

Research team(s)

Project type(s)

• Research Project

Abstract

Age-Related Hearing Impairment (ARHI), the most prevalent sensory impairment in the elderly, is a complex disease caused by environmental and genetic factors. Our laboratory recently identified two susceptibility genes for ARHI, GRHL2 and GRM7. The current project will elaborate the role of these two genes for the development of ARHI by genetic and functional studies.

Researcher(s)

• Promoter: Van Camp Guy
• Promoter: Van Laer Lut
• Co-promoter: Van Camp Guy
• Fellow: Bonneux Sarah

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand EU. UA provides EU research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut
• Fellow: Op de Beeck Ken

Research team(s)

Project type(s)

• Research Project

Abstract

The objective of this project is to find genes involved in age-related hearing impairment, nloise-induced hearing loss and otosclerosis. In a genome-wide association study, affected and non-affected persons are genotyped for hundred thousends of genetic variants across the entire genome. These variants are tested for association with the affection status. Apart from classical statistical tests, we will apply new analysis methods that are only possible if whole genome data are available.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Fransen Erik

Research team(s)

Project type(s)

• Research Project

Abstract

Since about ten years the focus of human genetics is shifting from monogenic diseases to complex or multifactorial diseases. Complex diseases, unlike monogenic diseases, do not show a simple Mendelian inheritance pattern but are caused by an interplay between genetic factors, environmental factors (including life style) and chance. Genome-wide association studies that aim to identify genes involved in complex diseases, have become a reality due to recent technological and methodological developments . A crucial development has been the availability of DNA microarrays that allow automated genotyping of 100,000s of genetic markers in a single subject. There are several factors that determine the success of such genome-wide studies. There is evidence that isolated populations are particularly suited for genetic association studies. This PhD project aims to: 1.) Evaluate the potential for genome-wide association studies in an isolated population in Finland: the Saami. 2.) Elucidate the genetic relationship between Saami, Finns and Western-Europeans. 3.) Development an R package for the analysis of genome-wide association studies. Concretely: a) new statistical methods will be programmed that correct for dependency between subjects and inbreeding, two problems associated with the analysis of genetic data coming from isolated populations, and b) the implementation of methods for the analysis of copy number variants.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Huyghe Jeroen

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut
• Fellow: Op de Beeck Ken

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing impairment is a common handicap which can have far reaching social and psychological consequences. According to the latest statistics from neonatal hearing screening, congenital hearing loss in Flanders occurs in approximately 1 in 700 newborns. In more than half of the cases the hearing impairment is caused by a mutation in a single gene (monogenic). Presently approximately 40 different genes have been identified as responsible for nonsyndromic monogenic hearing impairment, but the majority of genes remain unidentified. Hereditary hearing impairment is therefore an extreme example of genetic heterogeneity. Hearing loss which occurs later in life is far more frequent than hearing loss which occurs in young children. As opposed to hereditary hearing impairment in children, which is almost always monogenic, hearing impairment which occurs later in life is a complex condition caused by a combination of genetic and environmental factors. Age-related hearing loss, noiseinduced hearing impairment and otosclerosis are the most frequent forms of complex hearing impairment. However, to date no genetic risk factors have been identified. For 10 years our laboratory has been localizing and identifying genes by positional cloning. Although this is continued in this project, this forms an increasingly smaller part of the project. The emphasis for monogenic conditions is more on the characterisation of genes and on the elucidation of the pathophysiological mechanisms that lead to hearing loss. Here, the emphasis lies on DFNA5 and TGF-beta. Mouse models play an important role in this functional analysis. We have gained valuable experience with mouse models for hereditary deafness in our laboratory with the analysis of a DFNA5 knockout model (Van Laer et al, Neurobiol Dis 19, 386-399, 2005) and a TECTA knockout (Legan et al, Nature Neurosci, 8:1035-42, 2005). A second part that is growing in importance in our research makes use of techniques for the analysis of complex diseases. Within the framework of this project these techniques will be used for the identification of genes that modify the phenotype of GJB2 patients, the most frequent form of hereditary deafness.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Otosclerosis is a common bone disorder of the otic capsule, which usually results in a conductive hearing loss due to fixation of the stapes. Otosclerosis has a prevalence of 0.3-0.4% among white adults. The etiology of otosclerosis is unknown, and both genetic and environmental factors have been implicated. At the moment, three autosomal dominant loci have been localized, but none of the responsible genes has been identified. De purpose of the project is twofold. On the one hand traditional positional cloning techniques will be used to identify genes for monogenic forms of otosclerosis. The gene localization starts with a genome-wide scan in a large Greek family. Candidate genes will be selected in the candidate interval by screening gene-databases or by using exon-prediction programs followed by RT-PCR analysis. Mutation screening will lead to the identification of the disease-causing gene. On the other hand genetic factors involved in the complex forms of otosclerosis will be identified via model-free linkage-analysis in 500 already collected samples from small families. Subsequently we will carry out a case-control association study in selected candidate genes, using Single Nucleotide Polymorphism (SNP) genotyping.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Thys Melissa

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Schrauwen Isabelle

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we try to identify genes that cause hearing loss in large families with nonsyndromic autosomal dominant or autosomal recessive hearing loss. We use the strategy of positional cloning to identify the disease-causing mutation. In addition, we try to identify modifier genes for connexin 26-related hearing loss. For this project, we collect patient homozygous for the 35delG mutation which have a large variation in the degree of hearing loss. We try to identify genetic modifiers that cause part of this variation by performing association studies.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Hilgert Nele

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to elucidate the genetic risk factors for complex forms of hearing impairment (age-related hearing impairment, noise-induced hearing loss and otosclerosis). In particular, we will analyze the data from high-throughput genotyping of large sample sets using statistical and epidemiological methods. Single SNP association, gene-gene interaction and gene-environment interactions will be tested.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Fransen Erik

Research team(s)

Project type(s)

• Research Project

Abstract

The main objective of this project is to acquire insight into the development of complex types of hearing loss, more specifically of ARHI (Age-Related Hearing Impairment) and NIHL (Noise-Induced Hearing Loss), through the identification of the susceptibility genes that are involved.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

Age-related hearing impairment is the most frequent sensory disability. It is a complex disease caused by an interaction between environmental and genetic factors. Up to now not much is known regarding the genetic factors involved in age-related hearing impairment. This project aims at the identification of genetic factors using a whole genome association study with the Affymetrix 500k SNP array on samples that have been collected in seven European countries.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims at the identification and characterization of genes involved in 3 frequent types of hearing loss: age-related hearing impairment, noise-induced hearing loss and otosclerosis. To achieve this, association studies will be performed on large sample collections. Confirmed susceptibility genes will be functionally characterized by relevant in vitro tests and an animal model. These results will be the basis for improved therapies for hearing loss.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul
• Co-promoter: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Van Camp Guy

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

This project comprises the functional study of KCNQ4, one of the genes responsible for progressive hearing impairment. The main goals are: the identification of the promotor elements and the construction and characterisation of a knock-out mouse. We will also investigate whether KCNQ4 plays a role within complex hearing impairment disorders.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut
• Fellow: Van Eyken Els

Research team(s)

Project type(s)

• Research Project

Abstract

Otosclerosis is a common bone disorder of the otic capsule, which usually results in a conductive hearing loss due to fixation of the stapes. Otosclerosis has a prevalence of 0.3-0.4% among white adults. The etiology of otosclerosis is unknown, and both genetic and environmental factors have been implicated. At the moment, three autosomal dominant loci have been localized, but none of the responsible genes has been identified. De purpose of the project is twofold. On the one hand traditional positional cloning techniques will be used to identify genes for monogenic forms of otosclerosis. The gene localization starts with a genome-wide scan in a large Greek family. Candidate genes will be selected in the candidate interval by screening gene-databases or by using exon-prediction programs followed by RT-PCR analysis. Mutation screening will lead to the identification of the disease-causing gene. On the other hand genetic factors involved in the complex forms of otosclerosis will be identified via model-free linkage-analysis in 500 already collected samples from small families. Subsequently we will carry out a case-control association study in selected candidate genes, using Single Nucleotide Polymorphism (SNP) genotyping.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Thys Melissa

Research team(s)

Project type(s)

• Research Project

Abstract

Noise-induced hearing loss is one of the most important occupational diseases in industrialized countries. It is a complex disease caused by an interaction between genetic and environmental factors. Up to now, little or nothing is known about the responsible genetic factors. Using association studies with genetic variations in several candidate-genes, we try to identify susceptibility-genes. When a causative variant has been identified, we will proceed with a thorough functional characterisation of the gene and the development of a mouse-model.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Konings Annelies

Research team(s)

Project type(s)

• Research Project

Abstract

EuroHear has two inter-related objectives. The first aim is to provide fundamental knowledge about the development and functioning of the inner ear by studying the hair bundle, hair cell ribbon synapses, outer hair cell motility and potassium homeostasis. The second aim is to identify the genes underlying hereditary hearing impairment (HI) in both humans (monogenic HI and presbycusis) and mice. In addition, Eurohear focusses on the standardisation, implementation and development of technologies and on the development of new preventive and therapeutic tools for HI.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Hilgert Nele

Research team(s)

Project type(s)

• Research Project

Abstract

Otosclerosis is a common bone abnormality of the otic capsule, characterized by abnormal resorption and redeposition of bone. Two types of otosclerosis can be distinguished: histological and clinical otosclerosis. Histological otosclerosis refers to the presence of otosclerosis, diagnosed post mortem by histological survey of temporal bones. Clinical otosclerosis refers to the presence of conductive or mixed hearing loss caused by stapedial fixation or round window abnormalities. An important discrepancy exists in the prevalence of both forms, 2.5% for histological otosclerosis and 0.3% for clinical otosclerosis, respectively. Therefore, otosclerosis is clearly under-diagnosed in clinical practice (factor 8!). This discrepancy between histological and clinical otosclerosis is caused by the variable topography of the otosclerotic foci in the otic capsule: not all localisations cause a typical symptomatology. A fenestral otosclerosis (oval or round window) is relatively easily diagnosed with audiometrical and tympanometrical techniques. In this case, a conductive or mixed hearing loss is present, whether with or without a typical Carhart notch. When the otosclerotic foci occur somewhere else in the otic capsule, the so called `cohlear otosclerosis' is difficult to distinguish audiometrically from other forms of perceptive hearing loss. By using radiological imaging techniques, the diagnosis of cochlear otosclerosis can be made in some cases, but usually no radiological symptoms are visible. In conclusion, due to the high prevalence among the population there is a current need for a more sensitive and more specific diagnosis of cochlear otosclerosis, both clinically as well as radiologically. In addition, otosclerosis appears to be a genetically complex disease caused by an interaction of genes and environmental factors. However, knowledge regarding the influence of this interaction is insufficient, but is probably partially underlying the heterogeneous fenotypic characteristics. Further classification of these otosclerotic subfenotypes is a conditio sine qua non for the clinical diagnostics. When scientific research succeeds in pin-pointing environmental or genetic risk factors and correlating these factors with fenotypic characteristics the foundation is laid. The fundamental insights in the aetiology of otosclerosis and the more concrete classification of otosclerosis-subfenotypes gained by this project, will allow the ORL-clinicians to make a more specific diagnosis. In this way, the current symptomatic approach of otosclerosis will evolve to a more individual-specific approach.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Parizel Paul
• Co-promoter: Van Camp Guy
• Fellow: Van Den Bogaert Kris

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Age-related hearing impairment is the most frequent sensory disability. It is a complex disease caused by an interaction between environmental and genetic factors. Up to now not much is known regarding the genetic factors involved in age-related hearing impairment. This project aims at the identification of genetic factors using association studies on candidate genes with samples that will be collected in three Flemish centres (Antwerp, Ghent and Brussels).

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing impairment (HI) is a frequent clinical problem in humans and affected individuals experience deterioration in their communication skills. Since the beginning of the 90s, tremendous progress has been achieved in the understanding of the genetic causes of hereditary HI. This progress, however, is mainly limited to rare, monogenic forms of HI. The etiology of relative frequent forms, such as noise-induced hearing loss (NIHL), is more complex. Up to now, little research has been performed on the genetic factors responsible for these complex forms. NIHL is the second most common form of sensorineural HI, after presbyacusis. Remarkably, the individual susceptibility to NIHL varies greatly. This inter-individual variability is due to an interaction of susceptibility genes and environmental factors. At the moment, a few environmental factors are known to cause a raised susceptibility, including exposure to organic solvents and heavy metals. Laboratory studies have shown that a synergistic effect exists between noise exposure and exposure to chemicals. Furthermore, some studies have demonstrated that individual factors such as smoking, elevated blood pressure, and cholesterol levels may influence the degree of NIHL. In contrast to environmental factors, nothing is currently known about the genetic basis of NIHL. The purpose of this project is to identify genes that cause a raised susceptibility to NIHL. Prof. Dr. Mariola Sliwinska-Kowalska will be responsible for data and DNA sample collection. Within the framework of the NOPHER and NOISECHEM projects, she possesses an extensive database with information concerning the audiometric status, noise exposure, and exposure to chemicals, from 1500 Polish workers. Since the development of NIHL is related to gender, a distinction is made between male and female workers and afterwards individuals are categorized into 3 age groups (<35y, 35-50y, ³51y). Within each age group, individuals are divided into 3 exposure groups (<85dB, 85-91dB, ³92dB). Subsequently, hearing thresholds at the most relevant frequenies (4 and 6 kHz) are evaluated, and for each of the possible subgroups individuals are selected at the two extremes of the phenotypic spectrum viz. 10% most susceptible and 10% most resistant subjects. The selection of patients at the two extremes of the phenotypic spectrum has the advantage of providing a much higher power for the identification of the underlying genes and it reduces the number of samples to be analyzed. To identify the genetic risk factors, an association study will be performed by Single-Nucleotide Polymorphism (SNP) genotyping. SNPs are DNA sequence variations that involve a single nucleotide in the human genome. SNPs have been proposed as efficient tools for the analysis of complex diseases. If a certain SNP allele confers susceptibility to NIHL, it is expected that this SNP allele is more frequent among susceptible individuals compared to resistant individuals. The disease-associated allele may be the direct cause of the disease or it may be in linkage disequilibrium with the disease-causing mutation. As association analysis of the total genome by SNP genotyping would lead to unrealistically high number of SNP analyses, even with efficient high throughput screening methods, we will limit the analysis to SNPs located in candidate genes. Excellent candidates for susceptibility to NIHL are all known genes responsible for monogenic HI, which are also natural candidates for the involvement in complex forms of HI. Genes that protect against oxidative stress and mitochondrial genes can also be considered as important candidates since it is well known that oxidative stress plays a substantial role in the development of NIHL. In addition, a possible association between NIHL and glutathione S-transferase µ, an enzyme with an important anti-oxidative function, has already been described by Rabinowitz et al. (Hearing Res. 2002; 173: 164-171).

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing loss is the most frequent sensory disability. Age-related hearing impairment (ARHI) is a problem for approximately 50% of the elderly. In addition, vestibular dysfunction is frequent: 3 to 5% of the population is faced with vertigo or dizziness during his lifetime. This project studies a complex type of hearing impairment (ARHI) through the identification of ARHI susceptibility genes as well as a monogenic type of hearing impairment through functional studies on the DFNA5 gene. Finally, the vestibular aspect will be studied through the identification and characterization of the gene responsible for the head bobbing phenotype of an ENU mutant mouse.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

Otosclerosis is a common bone disorder of the otic capsule, which usually results in a conductive hearing loss due to fixation of the stapes. Otosclerosis has a prevalence of 0.3-0.4% among white adults. The etiology of otosclerosis is unknown, and both genetic and environmental factors have been implicated. At the moment, three autosomal dominant loci have been localized, but none of the responsible genes has been identified. De purpose of the project is twofold. On the one hand traditional positional cloning techniques will be used to identify genes for monogenic forms of otosclerosis. The gene localization starts with a genome-wide scan in a large Greek family. Candidate genes will be selected in the candidate interval by screening gene-databases or by using exon-prediction programs followed by RT-PCR analysis. Mutation screening will lead to the identification of the disease-causing gene. On the other hand genetic factors involved in the complex forms of otosclerosis will be identified via model-free linkage-analysis in 500 already collected samples from small families. Subsequently we will carry out a case-control association study in selected candidate genes, using Single Nucleotide Polymorphism (SNP) genotyping.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Thys Melissa

Research team(s)

Project type(s)

• Research Project

Abstract

In the 21st century, Europe will face the burden of its ageing population. The most common sensory impairment among the elderly is age related hearing impairment (ARHI). In this project, we want to identify the ethological factors involved in ARHI, including the genetic causes, the environmental causes and the interaction between them. A large cohort of patients and controls, originating from various parts of Europe, will be subjected to audiologic evaluation, genetic analysis and a questionnaire on suspected environmental risks. We expect to identify the major susceptibility genes and clarify the role of environmental risk factors. The interaction between the different factors will be studied using neural network computing. Based upon these results, guidelines will be formulated for the prevention of ARHI.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

This project comprises the functional study of KCNQ4, one of the genes responsible for progressive hearing impairment. The main goals are: the identification of the promotor elements and the construction and characterisation of a knock-out mouse. We will also investigate whether KCNQ4 plays a role within complex hearing impairment disorders.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Eyken Els

Research team(s)

Project type(s)

• Research Project

Abstract

This project, that will be excecuted at the Centre of Medical Genetics at the University of Antwerp, has the purpose to gain more profound findings in the physiology of the hearing proces and the pathophysiology of hearing impairment. Hearing impairment is a common affection that can assume different forms. In this project we consider two families with hearing impairment. The indonesian family characteristically exhibits loss of the high frequencies with a progression to the complete spectrum of frequencies. The gene responsible for the hearing loss was localized on chromosome 1, in a region of 8 cM. Several candidate genes are already examined, although no disease causing mutation has been been found. A Dutch family exhibits loss of the middle frequencies without any progressive course. The disease causing gene in this family is localised nearby the COL11A2-gene that is already responsible for several forms of hereditary hearing impairment. Mutation analysis prouved that COL11A2 could not be responsible for the hearing impairment in this family. The strategy of this project, is greatly comparable in the two families. Only in the indonesian family a previous diminishing of the candate region will be realised by the analysis of markers on additional DNA-samples, who will be isolated during a stay in Indonesia. A further refinement in both families will be achieved by de analysis of additonal markers on the available DNA. The strategy of this project is mainly based on the results of the Human Genome Project where a large share of the sequence of the humane genome is already specified and many genes are already identified. At the moment however the sequence is incomplete and not accurate. When a part of the sequence is missing, a BAC-contig of this region will be constructed en will be offerd to the HGP for sequencing analysis. When the sequence is known, unknown genes can be predicted by computer analysis. Eventually a list of candidate genes can be drawn up and according to different criterions like expression in the inner ear and their presumable function there will be drawn up a rank for mutation analysis. When a gene is identified, we will investigate this gene on functional domains and will investigate the homology with other known genes. Also the pattern of expression will be examined. Eventually knock-out mice will be made of one of the two identified genes. Which gene will be used for the construction of the knock-out, depends on the moment of identification and the type of mutation. A detailed analysis of the knockout mouse will eventually acquire a deeper insight the function of the gene.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Snoeckx Rik

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to get a better insight in the molecular mechanisms involved in hearing and hearing impairment, by identifying genes responsible for hereditary hearing impairment. The specific aims are the identification of genes responsible for respectively low frequency, midfrequency and high frequency hearing impairment, on the basis of families with autosomal dominant hearing impairment of these 3 types, that show linkage to 3 different chromosomal regions.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul

Research team(s)

Project type(s)

• Research Project

Abstract

Among white adults otosclerosis is the single most common cause of hearing impairment. The disease is caused by abnormal bone homeostasis of the otic capsule, which usually results in a conductive hearing loss due to fixation of the stapes footplate, although sensorineural hearing loss also may occur. The etiology of otosclerosis is unknown, and both genetic and environmental factors have been implicated. Although the genetics of otosclerosis are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. Using two large families showing this type of Mendelian inheritance pattern, we have localized two otosclerosis-causing genes, OTSC1 and OTSC2. We also have shown that at least one additional locus exists. Continuing on this initial body of work, we propose to: 1)Clone the OTSC1 and OTSC2 genes; 2)Identify novel otosclerosis loci by linkage analysis; 3)Identify novel otosclerosis loci by linkage and linkage disequilibrium analyses in families from Greece; 4)Identify novel otosclerosis loci by non-parametric linkage analysis using affected sib pairs.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

1. Problem The most common sensory impairment among the elderly is age-related hearing impairment (ARHI), with a prevalence of around 50% at the age of 80. Research has already shown that ARHI is a complex disorder, influenced by environmental as well as genetic factors. However, the first ARHI gene has yet to be identified, and the role of environmental factors (noise, chemicals, drugs,') is not very clear. 2. Research outline and objectives A total of 300 isolated ARHI patients and 300 normal hearing controls are being collected as part of an ongoing ASPEO project funded by the Flemish government. Each individual gives a blood sample for DNA extraction, and fills out a standardised questionnaire on his/her clinical history and on the exposure to environmental factors that may contribute to ARHI. The project presented here uses the same cohort of patients to identify the genetic causes of ARHI. Several genes that have a known role in hearing will be analysed. We will look for DNA variations that are common among ARHI patients but rare among controls, which indicates a causative role for this gene in ARHI. Integration of the data obtained in this study, combined with the results from the environmental study, may shed a light on the interaction between genetic and environmental factors contributing to ARHI. 3. Expected achievements 1) Improved knowledge of the ageing process in the inner ear. A better understanding of the basic molecular and cellular processes of ageing may uncover previously unrecognised factors leading to ARHI or new therapeutic pathways. 2) Recommendations for prevention of ARHI. As the different components contributing to ARHI are clarified, more precise guidelines can be formulated to prevent or delay its onset. Certain environmental risk factors may be harmful only to a limited number of individuals, depending on their genetic background. 3) Improvement of treatment. Attempts to develop gene therapy are hampered by a lack of knowledge of aethiological factors and genes involved. The data resulting from this project will be a first step towards future development of gene therapeutic approaches for hearing impairment, and to a pharmacogenomic approach of this condition ' i.e adapting drugs to an individual's genetic background

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

This project clusters four research teams of the Center of Medical Genetics at the University of Antwerp in the field of bone disorders, hereditary deafness, mental retardation and psychiatric genetics. The general aims, shared over the different research topics are localisation of disease causing genes, identification of disease causing genes, functional analysis of newly identified genes, and exploring therapeutic possibilities in animal models, based on the results of the functional analysis.

Researcher(s)

• Promoter: Nöthen Markus
• Promoter: Van Camp Guy
• Co-promoter: Kooy Frank
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

DFNA5 is a gene for an autosomal dominant form of hearing impairment. Up to now, no function could be assigned to the DFNA5 gene product. This project aims to contribute to the elucidation of the DFNA5 function using a combination of immunohistochemical and in-situ hybridization studies on inner ear, the subcellular localization of the protein, the identification of interacting proteins, a thorough study of a DFNA5 knockout mouse, and the evaluation of DFNA5 function from organ of Corti primary cell cultures.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

The overall long-term objective of this new project is to network a collaborative work on genetic deafness in Europe. The specific goals are: Studies on Connexin 26 that is the most common gene involved in non-syndromal severe hearing impairment. Usher syndrome and other syndromes causing deaf-blindness. A study on mechanisms involved in mitochondrial deafness Study the genotype/phenotype correlation Psychosocial consequences of genetic hearing impairment To spread the information about the work done to medical personnel involved, associations and families.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing impairment is a handicap that can seriously limit the communication skills of the affected individual. Hearing impairment is divided into two types: conductive (caused by abnormalities in the conduction of sound in the outer or middle ear) and sensorineural hearing loss (due to defects in the perception of sound in the inner ear). Otosclerosis is a progressive hearing impairment, characterised by conductive hearing loss due to a fixation of the stapes in the oval window. Clinical otosclerosis has a prevalence of 0.2-1% among white adults. Although stapes microsurgery has proven to be a successful means to improve hearing thresholds, otosclerosis gives rise to a considerable morbidity. Epidemiological studies indicate autosomal dominant inheritance with reduced penetrance, but on the other hand a viral etiology has also been suggested. However, the etiology of otosclerosis is poorly known and its genetics is poorly understood. At the moment, this lack of knowledge is the most important obstacle for the development of better therapies or prevention possibilities. The first objective of this project is to identify and study a gene, responsible for otosclerosis on the basis of a large multigenerational Flemish family in which otosclerosis is inherited autosomal dominantly. First, a genome wide screen will be performed to localise the gene concerned. The localisation of this gene will be refined by the analysis of additional genetic markers and additional Flemish families. Subsequently, we will look for candidate genes in this region and perform mutation analysis to identify the otosclerosis gene. We will try to identify functional domains and homologues by computer analysis of the DNA sequence of this gene and construct a mouse model for otosclerosis. By Northern blot, RT-PCR, in situ hybridisation and immunocytochemistry, the expression of the otosclerosis gene will be studied. The second objective of this project is to analyse a possible viral cause of otosclerosis. PCR analysis will be performed to detect measles virus in bone specimens from the middle ear of otosclerosis patients and control patients to investigate a possible correlation between the presence of measles virus and the disease.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Den Bogaert Kris

Research team(s)

Project type(s)

• Research Project

Abstract

Presbycusis is a frequent complex disease that is caused by a combination of environmental factors and genes. In this project presbycusis patients and controls will be analyzed in a case-control (linkage disequilibrium) association study to identify the susceptibility genes involved in presbycusis. This is done by Single-Nucleotide Polymorphism (the latest generation of genetic markers that arose from the Human Genome Project) genotyping in carefully selected functional candidate genes.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing impairment is a frequent handicap that can have profound social and psychological effects. Depending on which part of the hearing system that is damaged, conductive and sensorineural hearing loss can be distinguished. Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, which usually results in a conductive hearing loss due to fixation of the stapes footplate, although sensorineural hearing loss also may occur. Clinical otosclerosis has a prevalence of 0.3 0.4% among white adults. Although there are families with autosomal dominantly inherited otosclerosis, it is a complex disease in most cases, involving genetic as well as environmental factors. However, none of these factors are currently known. This lack of knowledge is the main obstacle to improve the morbidity involved by this disease. Until now three loci for autosomal dominant otosclerosis, respectively OTSC1 (15q25-26), OTSC2 (7q34-36) and OTSC3 (6p21.2-22.3), have been found, but the genes have not been identified yet. In addition, most families don't show linkage to OTSC1, OTSC2 and OTSC3 indicating that there must be additional loci for otosclerosis. The specific aim of the study is to identify novel otosclerosis genes by conventional parametric linkage analysis as well as by non-parametric linkage analysis. Parametric linkage analysis will be carried out on two large autosomal dominant otosclerosis families. First a genome search, in cooperation with the MDC-Gene Mapping Centre of Berlin, will be performed in the two families to localize the otosclerosis genes. The resulting candidate regions will be refined by analysis of additional markers. Subsequently, mutation analysis will be performed on candidate genes in these regions to identify the otosclerosis genes. Computer analysis of the DNA sequence and analysis of the expression pattern will help to identify a possible function for the protein. A second part of the project aims at the identification of novel otosclerosis genes by non-parametric linkage analysis using a large collection of small families and association study on unrelated patients. The main method of non-parametric linkage will be affected sib pair analysis. A total genome scan will identify genomic regions that contain genes involved in the etiology of otosclerosis. In these regions potential candidate genes will be selected. These genes will be tested in an association study using Single Nucleotide Polymorphism (SNP) genotyping in a set of unrelated patients and matched controls. Genes showing association will be sequenced in order to identify the disease-causing variant. Using these methods, we aim to identify one or more genes for otosclerosis.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Faghel Carole

Research team(s)

Project type(s)

• Research Project

Abstract

The inner ear contains the organs for hearing (the cochlea) and balance (the vestibulum). The cochlea and the vestibulum are evolutionary related and their functioning is similar, but not yet fully understood. A better understanding of these organs can lead to better treatments for patients suffering from hearing impairment or imbalance problems. The aim of this study is to obtain a better understanding of the functioning of the inner ear by searching and characterizing genes involved in hearing impairment and vestibular dysfunction. Specific aims include: i) positional cloning of disease genes in families with hereditary hearing loss and vestibular dysfunction ii) construction and characterization of cDNA libraries for the cochlea and the vestibulum iii) characterization of genes involved in hearing and balance using histologic and biochemical techniques.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Fransen Erik

Research team(s)

Project type(s)

• Research Project

Abstract

The physiology of the ear, and the molecular mechanisms that underlie it are poorly known. Hearing impairment has a genetic cause in many cases, but at this moment relatively little is know about the responsible genes. The general aim of this project is to acquire a better understanding of the molecular mechanisms involved in hearing and hearing impairment by means of identification and characterization of genes for hereditary hearing impairment. The specific aims are: Localization and identification of a gene for otosclerosis, localization of the responsible gene in the Ecl mouse with vestibular dysfunction, identification of deafness genes, functional studies of deafness genes and the construction of mouse models.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

This project, that will be excecuted at the Centre of Medical Genetics at the University of Antwerp, has the purpose to gain more profound findings in the physiology of the hearing proces and the pathophysiology of hearing impairment. Hearing impairment is a common affection that can assume different forms. In this project we consider two families with hearing impairment. The indonesian family characteristically exhibits loss of the high frequencies with a progression to the complete spectrum of frequencies. The gene responsible for the hearing loss was localized on chromosome 1, in a region of 8 cM. Several candidate genes are already examined, although no disease causing mutation has been been found. A Dutch family exhibits loss of the middle frequencies without any progressive course. The disease causing gene in this family is localised nearby the COL11A2-gene that is already responsible for several forms of hereditary hearing impairment. Mutation analysis prouved that COL11A2 could not be responsible for the hearing impairment in this family. The strategy of this project, is greatly comparable in the two families. Only in the indonesian family a previous diminishing of the candate region will be realised by the analysis of markers on additional DNA-samples, who will be isolated during a stay in Indonesia. A further refinement in both families will be achieved by de analysis of additonal markers on the available DNA. The strategy of this project is mainly based on the results of the Human Genome Project where a large share of the sequence of the humane genome is already specified and many genes are already identified. At the moment however the sequence is incomplete and not accurate. When a part of the sequence is missing, a BAC-contig of this region will be constructed en will be offerd to the HGP for sequencing analysis. When the sequence is known, unknown genes can be predicted by computer analysis. Eventually a list of candidate genes can be drawn up and according to different criterions like expression in the inner ear and their presumable function there will be drawn up a rank for mutation analysis. When a gene is identified, we will investigate this gene on functional domains and will investigate the homology with other known genes. Also the pattern of expression will be examined. Eventually knock-out mice will be made of one of the two identified genes. Which gene will be used for the construction of the knock-out, depends on the moment of identification and the type of mutation. A detailed analysis of the knockout mouse will eventually acquire a deeper insight the function of the gene.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Snoeckx Rik

Research team(s)

Project type(s)

• Research Project

Abstract

Although vertigo or dizziness is commonly encountered in otological practice, the aetiology still remains obscure. A better understanding of the pathological mechanisms of vestibular dysfunction is important for the development of new and better therapies. At this moment, the molecular knowledge of vestibular function is limited. Moreover, the genes responsible for the development and function of the vestibular apparatus are unknown. It is currently very difficult to identify these genes through studies of human patients. The two most important reasons for this are the lack of suitable families and the complex inheritance of vestibular dysfunction. Mouse models can be used, however. The anatomy of the mouse inner ear is very similar to the human one, the genetic maps of mice and men show strong homology, and mice can be bred very easily. The purpose of this project is to identify and study genes, responsible for vestibular dysfunction on the basis of a mouse with vestibular dysfunction, called epistatic circler (ecl). When two independent inbred strains (C57L/J and SWR) are crossed, mice with circling behaviour appear in the second generation. The circling behaviour is probably attributed to two interacting loci: ecl (epistatic circling gene of C57L/J) and ecs (epistatic circling gene of SWR). First, a genome wide screen will be performed to localise the ecl- and ecs-genes. The localisation of these genes will be refined by the analysis of additional genetic markers in 100 ecl mice. Subsequently, we will look for candidate genes in this region and perform mutation analysis to identify the ecl- and ecs-genes. We will try to identify functional domains and homologues by computer analysis of the DNA sequence of these genes. By Northern blot, RT-PCR and in situ hybridisation, the expression of the ecl- and ecs-genes will be studied. Behavioural studies of the mice will be performed to characterise the effect of the vestibular dysfunction on behaviour. We will perform a detailed morphological analysis of the inner ear of ecl mice by light and electron microscopy and by CT-scanning. Finally, we will correlate the data from genetical, behavioural and morphological studies.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Cryns Kim

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing impairment is a handicap that can seriously limit the communication skills of the affected individual. Hearing impairment is divided into two types: conductive (caused by abnormalities in the conduction of sound in the outer or middle ear) and sensorineural hearing loss (due to defects in the perception of sound in the inner ear). Otosclerosis is a progressive hearing impairment, characterised by conductive hearing loss due to a fixation of the stapes in the oval window. Clinical otosclerosis has a prevalence of 0.2-1% among white adults. Although stapes microsurgery has proven to be a successful means to improve hearing thresholds, otosclerosis gives rise to a considerable morbidity. Epidemiological studies indicate autosomal dominant inheritance with reduced penetrance, but on the other hand a viral etiology has also been suggested. However, the etiology of otosclerosis is poorly known and its genetics is poorly understood. At the moment, this lack of knowledge is the most important obstacle for the development of better therapies or prevention possibilities. The first objective of this project is to identify and study a gene, responsible for otosclerosis on the basis of a large multigenerational Flemish family in which otosclerosis is inherited autosomal dominantly. First, a genome wide screen will be performed to localise the gene concerned. The localisation of this gene will be refined by the analysis of additional genetic markers and additional Flemish families. Subsequently, we will look for candidate genes in this region and perform mutation analysis to identify the otosclerosis gene. We will try to identify functional domains and homologues by computer analysis of the DNA sequence of this gene and construct a mouse model for otosclerosis. By Northern blot, RT-PCR, in situ hybridisation and immunocytochemistry, the expression of the otosclerosis gene will be studied. The second objective of this project is to analyse a possible viral cause of otosclerosis. PCR analysis will be performed to detect measles virus in bone specimens from the middle ear of otosclerosis patients and control patients to investigate a possible correlation between the presence of measles virus and the disease.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Den Bogaert Kris

Research team(s)

Project type(s)

• Research Project

Abstract

Environmental as well as hereditary factors are involved in the aetiology of hearing loss. It has been demonstrated for two of these environmental factors, noise and ototoxic medicines, that the pathogenic processes leading to hearing loss result from the oxidative stress caused by reactive oxygen species and free radicals. Through the study of genes segregating in families with pure genetic hearing loss, scientists try to gain insight into the hereditary factors involved in hearing loss. DFNA5 is such a gene. Our research team was able to localise and subsequently identify the DFNA5 gene. The physiological function of the DFNA5 gene remains unknown, however preliminary experiments have shown that DFNA5 probably plays a role in the protection against oxidative stress. As a consequence, DFNA5 might be the missing link that connects the environmental and the hereditary factors involved in hearing loss. The first goal of this project is to definitely establish the involvement of the DFNA5 gene in the protection against oxidative stress. Subsequently, a DFNA5 knockout mouse will be thoroughly evaluated. When the DFNA5 knockout mouse turns out to be a good model for hearing loss, a number of therapeutic applications for various forms of hearing loss (noise-induced damage, ototoxicity, hereditary hearing loss, age-related hearing loss) will become obvious. The goals concerning these therapeutic applications will be completely elaborated in an application for a participation in a new EC-research project.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Hearing impairment is one of the most frequent sensory handicaps. Until the beginning of the 9O's 1itt1e was known about the molecular mechanisms responsible for the complex process of hearing and the pathology of hearing loss. However, the last few years fast progression has been made due to molecular genetics. Up to now, 48 genes for non- syndromic hearing loss have been localized, confirming the predicted genetic heterogeneity .Only 11 genes have been identified so far . Recently, the DFNAS genewas identified in our research group (Van Laer et al., Nature Genet. 20,194-197,1998). DFNAS segregates according to an autosomal dominant inheritance pattem in an extended Dutch family with more than 100 affected family members. The family has been clinicaIly studied since the 60's. The hearing intpairment is non-syndromic, there were never any additional symptoms reported in the family. The progressive sensorineural hearing loss starts at an age between S and 15 years at the high frequencies. Only at older ages the lower frequencies become affected as weIl. The disease-causing mutation in the Dutch family is a complex intronic mutation in the DFNAS gene resulting in exon 8 skipping and leading to a frame shift and a premature protein truncation. Low expression levels of the DFNA5 gene were found in aIl the tissues that were investigated. Furthermore, DFNAS expression could be demonstrated in the cochlea. It remains unclear how mutations in a ubiquitously expressed gene can lead to hearing intpairment as the only phenotype. In spite of extensive computational analysis, no putative physiological function could be assigned to DFNA5.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

The emphasis of the project will shift towards the functional analysis of the genes, that were identified and transgenic mice and knockout mice will play a major role in this. Additional aspect of the project will be the study of genes that affect balance as well as hearing. The reason is obvious : the organs responsible for hearing and balance are the cochlea and the vestibulum, two evolutionary closely related components of the inner ear.

Researcher(s)

• Promoter: Dumon Jan
• Fellow: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

By the age of 75 years more than half of the population over 75 has a significant hearing loss, limiting their communicative skills. The study of the complex interactions between genes and environmental factors that are responsible for this hearing loss, is virtually impossible with current technology. However, families have been described with a pure genetic hearing loss that is very similar to the hearing loss of the elderly, but manifests itself at an earlier age. As gene localizations by linkage analysis are possible in these families, they offer unique possibilities for the identification of genes involved in progressive hearing loss. This should lead to a better insight in the pathological processes responsible for hearing loss, and to a better understanding of the physiology of hearing. This knowledge is a prerequisite for the development of better therapies for hearing loss. At this moment different gene localizations for autosomal dominant hearing loss have been published. Up to now none of these genes have been identified, and therefore, the function of these genes, and the mechanisms that lead to progressive hearing loss in these families remain unknown. For these reasons, a gene identification in the field of hereditary hearing loss will have a major scientific impact. In 1994 the Department of Medical Genetics in Antwerp started research in the field of hereditary hearing loss. In this period, we were able to localize a gene for autosomal dominant hearing loss to chromosome 1p, the DFNA2 gene. The general objective of this project is the identification of genes responsible for progressive hearing impairment. The major specific goal is the identification of the DFNA2 gene. Other families with hereditary hearing impairment will also be collected, and analysed.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

The inner ear contains the organs for hearing (the cochlea) and balance (the vestibulum). The cochlea and the vestibulum are evolutionary related and their functioning is similar, but not yet fully understood. A better understanding of these organs can lead to better treatments for patients suffering from hearing impairment or imbalance problems. The aim of this study is to obtain a better understanding of the functioning of the inner ear by searching and characterizing genes involved in hearing impairment and vestibular dysfunction. Specific aims include: i) positional cloning of disease genes in families with hereditary hearing loss and vestibular dysfunction ii) construction and characterization of cDNA libraries for the cochlea and the vestibulum iii) characterization of genes involved in hearing and balance using histologic and biochemical techniques.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

The general goal of this project is to obtain a better insight in the molecular mechanisms involved in hearing and hearing impairment, by identifying and characterizing genes for hereditary hearing impairment. The project compires functional studies of the TECTA gene, positional cloning of the DFNA2, DFNA5 and DFNAl0 genes, and analysis of mouse models for hereditary deafness.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul

Research team(s)

Project type(s)

• Research Project

Abstract

The inner ear contains the organs for hearing (the cochlea) and balance (the vestibulum). The cochlea and the vestibulum are evolutionary related and their functioning is similar, but not yet fully understood. A better understanding of these organs can lead to better treatments for patients suffering from hearing impairment or imbalance problems. The aim of this study is to obtain a better understanding of the functioning of the inner ear by searching and characterizing genes involved in hearing impairment and vestibular dysfunction. Specific aims include: i) positional cloning of disease genes in families with hereditary hearing loss and vestibular dysfunction ii) construction and characterization of cDNA libraries for the cochlea and the vestibulum iii) characterization of genes involved in hearing and balance using histologic and biochemical techniques.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Fransen Erik

Research team(s)

Project type(s)

• Research Project

Abstract

Although vertigo or dizziness is commonly encountered in otological practice, the aetiology still remains obscure. A better understanding of the pathological mechanisms of vestibular dysfunction is important for the development of new and better therapies. At this moment, the molecular knowledge of vestibular function is limited. Moreover, the genes responsible for the development and function of the vestibular apparatus are unknown. It is currently very difficult to identify these genes through studies of human patients. The two most important reasons for this are the lack of suitable families and the complex inheritance of vestibular dysfunction. Mouse models can be used, however. The anatomy of the mouse inner ear is very similar to the human one, the genetic maps of mice and men show strong homology, and mice can be bred very easily. The purpose of this project is to identify and study genes, responsible for vestibular dysfunction on the basis of a mouse with vestibular dysfunction, called epistatic circler (ecl). When two independent inbred strains (C57L/J and SWR) are crossed, mice with circling behaviour appear in the second generation. The circling behaviour is probably attributed to two interacting loci: ecl (epistatic circling gene of C57L/J) and ecs (epistatic circling gene of SWR). First, a genome wide screen will be performed to localise the ecl- and ecs-genes. The localisation of these genes will be refined by the analysis of additional genetic markers in 100 ecl mice. Subsequently, we will look for candidate genes in this region and perform mutation analysis to identify the ecl- and ecs-genes. We will try to identify functional domains and homologues by computer analysis of the DNA sequence of these genes. By Northern blot, RT-PCR and in situ hybridisation, the expression of the ecl- and ecs-genes will be studied. Behavioural studies of the mice will be performed to characterise the effect of the vestibular dysfunction on behaviour. We will perform a detailed morphological analysis of the inner ear of ecl mice by light and electron microscopy and by CT-scanning. Finally, we will correlate the data from genetical, behavioural and morphological studies.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Cryns Kim

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims at the identification of genes for human hereditary disorders by positional cloning. The physiological function and the underlying pathogenic mechanisms will be studied. The project will focus on the fragile X-syndrome, deafness and bone dysplasias.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The general goal of this project is the identification of genes responsible for progressive hearing loss The identification of these genes will improve our understanding of the pathological processes respo n sible fo r hearing i mpairment, and win leed to a bette r insight in the physiology of hearing. OFNA2 and DFNA5 are two loei on chromosome 1 and 7 respectively, where genetic linkage bas been found in families with autosomal dominant progressive hearing loss. The chromosomal regions in which the DFNA2 and OF'NAS genes are located have been reduced to a region of less than I million basepairs. The specific aim of this project is the identification of the DFNA2 and DFNA5 genes using positional cloning techniques.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

We will study 3 families in which hearing loss is inherited in an autosomal dominant pattern. First, the known deafness genes will be analysed by linkage analysis. When all the genes are excluded, the new gene will be mapped on the human genome by a genome search. Once the localisation is known the new gene will be identified by exon trapping, CpG islands analysis, isolation of conserved sequences or direct selection of tissue specific cDNA libraries.When identified a mutation analysis will be performed.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Verhoeven Kristien

Research team(s)

Project type(s)

• Research Project

Abstract

Progressive deafness is a common disability in which genetic factors as well as enviromental factors are involved. The Centre of Medical Genetics studies five families with monogenic autosomal dominant progressive deafness. All these families are linked to the DFNA2 gene on the short arm of chromosome l.The candidate region of the DFNA2 gene is about 1 million basepares long. The aim of this project is to isolate the DFNA2 gene. Methods like exontrapping and cDNA selection will be applied to find genes in the candidate region. These genes will be examined for mutations in order to identify the DFNA2 gene. A functional analysis and the construction of transgenic mice will reveal the physiological function and the role in the pathology of deafness of the DFNA2 gene.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Van Hauwe Peter

Research team(s)

Project type(s)

• Research Project

Abstract

By constructing new lines of transgenic mice, the physiological function of the fragile X gene and the pathogenesis of the fragile X syndrome, the most frequent form of inherited mental retardation, will be studied. A mouse fine with a point mutation (lle 304 Asn) and a mouse fine with an unstable CGG repeat in the fragile X gene will be constructed by microinjection. The mouse fine with the pointmutation is anticipated to have a more severe phenotype than the knockout mouse that we already generated and studied. The line with the elongated CGG repeats enables studies of the mechanism and timing of repeat amplification in a mouse model. In addition, biochemical studies will be performed to study the possibility that FMR1 is involved in transcription. Moreover, the effect of selected drugs on the cognitive function and behaviour of the transgenic mice will be tested.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Deafness and hearing loss are frequent handicaps that have a genetic cause in many cases. At the department of Medical Genetics in Antwerp, a gene for hereditary hearing loss was localized to chromosome lp34 in 1994. At this moment, a total of 5 farnilies are known that are linked to this region. This project aims at the identification of the gene causing hearing loss in these families, using positional cloning techniques.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

A genome search is being performed using 250 markers of all autosomes to localize a gene encoding autosomal dominant deafness in a very large Indonesian family.

Researcher(s)

• Promoter: Dumon Jan
• Fellow: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

This project compires the design and maintenance of a web-site, containing a summary of the most relevant genetic data for hereditary hearing impairment. These data compire gene localizations and identifications for syndromic and nonsyndromic hereditary hearing impairment (http:/dnalab. www.uia.ac.be/dnalab/hhh).

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Using in situ hybridisation of cells from patients expressing the fragile site on chromosome 12, a yeast artificial chromosome (YAC) will be isolated that overspans this site. The sequence causing the fragile site, probably an elongated CGG repeat, will be cloned and the extend of repeat amplification in patients and control persons will be compared. The gene associated with the fragile site will be isolated and characterised, and its role in the pathogenesis of mental retardation and psychiatric disturbances studied by constructing a knockout mouse model.

Researcher(s)

• Promoter: Van Camp Guy
• Fellow: Schoepen Isabelle

Research team(s)

Project type(s)

• Research Project

Abstract

Identification of the amplification of a CGG trinucleotide repeat in the fragile X gene (FMR1) as the disease causing mutation has permitted molecular diagnosis of the mutation. DNA analysis provides a powerful approach to identify patients and carriers. However, since the isolation of the gene still little is known about the function of FMR1. We try to elucidate the physiologic function of FMR1 and the pathologic mechanisms leading to the abnormalities observed in fragile X patients.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of the project is the localization and identification of genes responsible for non syndromic deafness. The study of these genes will provide a better insight in the physiology of hearing, and the mechanisms leading to hearing loss. De specific objectives are the collection of families with hereditary hearing loss, the localisation of new deafness genes, and the cloning of these deafness genes.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul
• Co-promoter: Willems Patrick

Research team(s)

Project type(s)

• Research Project

Abstract

The genes, encoding x-linked hydrogephaly, x-linked liver glycogenosis, fucosidosis, the fragile x-syndrome and an autosomal dominant deafness are studied at the molecular level.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Martin Jean-Jacques
• Co-promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

A genome search is being performed using 250 markers of all autosomes to localize a gene encoding autosomal dominant deafness in a very large Indonesian family.

Researcher(s)

• Promoter: Willems Patrick
• Fellow: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

Using genetic linkage analysis, the chromosomal localisation of the gene causing deafness will be determined in an extende Indonesian family with non-syndromic hereditary deafness. Subsequently, the project will aim to isolate the gene.

Researcher(s)

• Promoter: Van Camp Guy

Research team(s)

Project type(s)

• Research Project

Abstract

A chromosome 21 specific gene library was constructed and DNA markers were isolated and regionally mapped in different regions on chromosome 21. Markers from the proximal part of the long arm were used to identify DNA polymorphisms which can be useful in the genetic analysis in Alzheimer's disease and Down syndrome.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: Van Camp Guy

Research team(s)

Project type(s)

• Research Project