Research Frank Kooy

Abstract

Autism Spectrum Disorders (ASD) display a wide array of symptoms including deficits in social communication, impaired cognition, and anxious and repetitive behaviors, which affects 1% of the human population. To date ADNP is one of the most frequent ASD-associated genes (~0,2% of all ASD cases). ADNP truncation mutations cause an autosomal-dominant autism spectrum Helsmoortel-Van der Aa syndrome with highly variable clinical presentations of autism, intellectual disability, dysmorphic facial features, deficits in multiple organ systems and patients frequently suffer of comorbidities including increased susceptibility to inflammation, or gastrointestinal disturbances. In order to understand how Adnp truncations provoke this broad spectrum of clinical ASD manifestations a novel genetic frameshift mutation Adnpmut mouse model was generated, of which neurological ASD manifestations align with observations in Helsmoortel-Van der Aa syndrome (HVDAS) patients, including exacerbated anxiety, repetitive behavior and cognitive deficits and altered expression of synaptic plasticity genes. Based on preliminary studies in our Adnpmut mouse model, our core hypothesis in this proposal is that Adnp mutations cause altered epigenetic profiles which trigger DNA damage inflammasome responses, leading to neuroinflammation that perpetuates ASD development. Given the high prevalence of gastrointestinal problems in patients with the ADNP-related disorder and the relevance of the gut-brain axis in neuropathology, we expect that disturbances in gut homeostasis may exacerbate inflammation and amplify severity of ASD symptoms in Adnpmut mice. Therefore, in this project, we will test our core hypothesis in naïve Adnpmut mice as well as after a dysbiosis- and inflammation-provoking intestinal infection. Specifically, we will 1) Define the contribution of neuroinflammation in ADNP-ASD pathology, 2) Define the contribution of Aim2 inflammasome signaling in ADNP-ASD pathology 3) Define epigenetic malfunctions of Aim2 inflammasome signaling in ADNP-ASD pathology 4) Evaluate viral and peptide-based therapeutics to alleviate inflammation and ameliorate ADNP-ASD manifestations. Demonstrating how gastrointestinal infections promote epigenetic DNA damage which exacerbates neuroinflammation and ASD symptoms will significantly broaden our understanding of highly variable HVDAS manifestations. From a societal point of view, a proof-of-concept that a gut infection can aggravate ADNP syndromic autism will open insights for clinicians as well as for patients themselves in how to understand, prevent or manage ASD symptoms or other neuroplasticity pathologies via gut-brain intervention strategies.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Kooy Frank
• Co-promoter: Pasciuto Emanuela
• Co-promoter: Wullaert Andy

Research team(s)

• Cell death signaling (CDS)

Project type(s)

• Research Project

Abstract

Establishing effective therapies for rare neurodevelopmental diseases remains one of the greatest challenges in molecular medicine. Although advances in next-generation sequencing technologies have led to the discovery of hundreds of novel genetic syndromes over the past decade, the development of individualized therapies continues to lag behind. Each rare disorder, while affecting a small group, contributes to a global burden estimated to impact over 300 million individuals. The complexity arises from the fact that these disorders, often caused by mutations in different genes, affect multiple cellular pathways, generating an overwhelming volume of data that must be analyzed to inform therapeutic strategies. Current drug interventions have seen limited success in translating promising preclinical findings into patient-ready treatments. The rapid rise of AI technologies, however, has the potential to transform this landscape. AI-driven algorithms are increasingly capable of navigating vast biomedical datasets, revealing drug candidates for rare diseases at an unprecedented pace. Many start-ups are already capitalizing on this potential, generating a flood of drug candidates for preclinical evaluation. However, this surge in candidate therapies has shifted the bottleneck from drug discovery to preclinical testing. Traditional murine test batteries are labor-intensive, expensive, and time-consuming, necessitating a standardized, scalable, and efficient platform to meet the growing demand for drug screening. We propose the development and commercialization of our Live Mouse Tracker (LMT) platform, a cutting-edge tool designed to address this critical need. The LMT system automates behavioral analysis, capable of tracking up to 39 different behaviors in groups of mice over 24-hour periods. This high-throughput capability provides a rapid and comprehensive assessment of drug efficacy in preclinical models. Our initial validation will focus on the fragile X syndrome, a widely studied neurodevelopmental disorder for which no effective treatment currently exists. By evaluating drugs that target multiple affected pathways simultaneously, we aim to pioneer a new approach to rare disease therapy development. During this project, we will validate the robustness of the LMT platform and extend it into a fully integrated service, as well as explore collaboration with other university partners to offer comprehensive preclinical drug testing solutions. This service platform has the potential to revolutionize the drug development pipeline, ensuring that AI-generated candidate drugs can be rapidly and reliably assessed, accelerating the path from bench to bedside. Through this initiative, we aim to bridge the gap between drug discovery and therapeutic application, bringing hope to millions of patients with rare neurological diseases.

Researcher(s)

• Promoter: Bittremieux Wout
• Co-promoter: Annear Dale
• Co-promoter: Kooy Frank

Research team(s)

• ADReM Data Lab (ADReM)

Project type(s)

• Research Project

Abstract

CGG short tandem repeats (STRs) are stretches of low-complexity, CG-rich, repetitive DNA that inherit unstably in pedigrees and play a role in neurodevelopmental disorders (NDDs). While CGG STRs are causative for several disorders, here, I hypothesise that the amount of NDDs, resulting from dynamic mutations in CGG STRs, is grossly underestimated. I focus on CGG STRs due to their role in NDDs and because of the epigenetic silencing of the repeat-containing genes. Using the latest repeat genotyping algorithms and the T2T-CHM13/hs1 reference assembly, I will catalogue the human CGG STRs. With an additional step of repeat detection in indel variant data, I aim to extend the CGG catalogue beyond the constraints of the reference. Further, I will use whole-genome sequencing (WGS) data to establish a population baseline of STR length and variation, before assessing NDD population WGS data to identify potentially pathogenic STRs. Once STR expansion targets are identified, a group of NDD trios will be experimentally investigated by long-read sequencing. Until now, the epigenetic changes accompanying STR mutations have been presented as an all-or-nothing effect. In this project, I will challenge this dogma and define epigenetic changes associated with the full range of CGG STRs lengths. In addition, I will explore the biological and functional role of CGG STRs by assessing their mosaic differences across different brain tissues and correlating this with transcriptomic data.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Kooy Frank
• Fellow: Annear Dale

Research team(s)

• Cell death signaling (CDS)

Project type(s)

• Research Project

Abstract

Resistance to stress and adversity is crucial because daily family life requires constant adaptation to changing challenging situations. This refers to resilience, which protects parents and children against the development of psychopathology. In light of this, there is an urge for research to underpin programs strengthening family resilience. We will study transmission of stress resilience between mother, father and child, to identify biobehavioral dynamics and factors contributing to resilience transmission in 500 families with children aged between 10 and 12 years. We start from the assumption that resilience transmission is a dynamic process whereby family members mutually affect each other's capacity to recover from stressful events. We predict that resilience transmission is related to biobehavioral family factors such as matching versus discordant family (epi-)genetic and endocrinological profiles, and family climate. We will also investigate whether transmission is linked to biobehavioral synchrony between family members. This latter refers to spontaneous synchronization between parent and child social behavior, their physiology, and between physiology of one and behavior of the other when confronted with stressors. Studying biobehavioral synchrony in the context of resilience transmission is highly innovative. It can lead to scientific breakthroughs, expanding our understanding of resilience and strategies to support families' resilience in the face of distress.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

• Medical Genetics (MEDGEN)

Project website

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

Dynamic mutations, stretches of repetitive DNA sequences that inherit unstably in pedigrees, are an important cause of intellectual disability and autism. In this project, we argue that the number of a specific class of dynamic mutations, the CGG-repeats is grossly underestimated. We focus in on CGG-repeats, as these have already been implicated in multiple disorders and moreover because these induce epigenetic silencing of associated repeats. Using the latest algorithms we will catalogue all repeats in the genome and annotate which ones are potentially prone to expansion. In a large patient cohort, we will search for expansions of any of those repeat. The repeat expansions will be experimentally validated. Up till now, the epigenetic changes accompanying dynamic mutations have been presented as an all or nothing effect. In this application, we will challenge this dogma and will more accurately define epigentic changes associated with the full range of CGG-repeats at several loci in the human genome. In addition, we will define one novel repeat expansion disorder by creating a cellular model and subject this to transcriptomic and neuronal network analysis. In summary, our project will increase our insights in the role CGG-repeats play in the human genome and in neurodevelopmental disease.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Vandeweyer Geert

Research team(s)

• Medical Genetics (MEDGEN)

Project website

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

Testing of repurposed drugs may lead to more effective treatment of core symptoms of Fragile X syndrome or in fact, of any neurological disorder. However, such an approach faces the challenge of having to test multiple drugs, likely in various concentrations each. This is a time-consuming and costly for current approaches, where preclinical testing is usually performed using large behavioral murine test batteries in combination with ex-vivo electrophysiological measurements. In this project, we propose to develop a highly versatile and innovative drug screening platform for Fragile X syndrome using a combination of live mouse tracker (LMT) and multi-electrode array (MEA). Standard behavioral test batteries will be replaced by a single LMT recording. This tracker is able to dissect up to 35 different behaviors of groups of up to four mice from a single 24-hour recording, providing a powerful first look at a drug's effectiveness. In addition, cultured primary neurons will be used for electrophysiological recordings of neuronal networks on the MEA. Drugs can be added on a daily basis, and the changes in the measures can assess the drugs. By combining LMT and MEA we aim to establish a ready-to-use, innovative and efficient drug screening platform for the preclinical validation of novel compounds and/or repurposed drugs for Fragile X syndrome, a prime example of a neurological disorder for translational medicine.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. The mutational basis of FXS is the abnormal expansion and consequent hypermethylation of a CGG trinucleotide repeat in the promoter region of the fragile X mental retardation 1 (FMR1) gene, leading to transcriptional silencing and absence of fragile X mental retardation protein (FMRP). Current treatment is symptomatic and no specific drugs are available for the disorder yet. Several animal models have been developed to study FXS, of which the Fmr1 knockout (KO) mouse is the most studied. Over the past decades multiple studies have indicated an important role of FMRP in multiple cellular pathways, and several potential therapeutics showed efficacy in reversing symptoms in predominantly the Fmr1 KO mouse model. Unfortunately, the successes of the preclinical evaluations were rarely matched in clinical trials. However, essentially only therapies with drugs targeting individual pathways have been initiated. This oversimplification by targeting only one pathway at a time suggests that the use of a combination therapy, targeting multiple involved pathways simultaneously, is a promising new strategy in drug discovery for FXS. However, such an approach faces the challenge of having to test multiple compounds and a combination of a series of drugs, likely in various concentrations each. Most studies demonstrated rescue of symptoms based on a battery of behavioral tests and electrophysiological recordings that differ from laboratory to laboratory. This current approach is labor intensive, time consuming and costly, and therefore not fitted to screen for multiple drugs, nor combination therapies, where multiple drugs in multiple dosages need to be combined. Therefore, we have developed a standardized method to measure the effectiveness of different drugs in a uniform and versatile screening protocol. For electrophysiological measurements we have selected the multi electrode array (MEA) system, that can be used to determine the effects Fmr1 deletion on electrophysiology and neural network functioning. For the behavioral analysis, we use live mouse tracker (LMT) 24h recordings. This system is able to dissect up to 35 different (social) behaviors of up to four mice from a single 24 hours recording, and provides a first glance of the effectiveness of a drug. By combining the MEA and LMT we have developed a versatile, high throughput, innovative and efficient drug screening platform for fragile X syndrome. Additionally, this platform is the first universal system that has the potential to test multiple drugs under identical conditions in a single (same) laboratory.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

• Medical Genetics (MEDGEN)

Project website

Project type(s)

• Research Project

Abstract

This is a gift that was awarded to expand our work on the Helsmoortel Van der Aa syndrome. It has been used, among other things, to facilitate the Neurodevelopmental disorders conference of September 2022.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

This project aims to upgrade the current electrophysiology technologies at UAntwerpen by acquiring a state-of-the-art MicroElectrode Array platform (MEA). To study the electrophysiological properties of excitable cells, currently patch-clamping is the gold standard. However, this is an extremely labour-intensive and invasive technique, limited to short-term measurements of individual cells at single time points. On the other hand, MEAs enable high-throughput non-invasive longitudinal real‐time measurements of functional cellular networks, without disrupting important cell-cell contacts, and thus provide a more physiologically relevant model. The multi-well format allows repeated recordings from cell cultures grown under various experimental conditions, including the opportunity to rapidly screen large drug libraries. Based on these advantages, multi-well MEAs are the most suitable instrument for functionally elucidating the pathomechanisms of neurological/cardiac disorders by performing (1) cardiac activity assays: measurement of field and action potentials from (iPSC-)cardiomyocytes to investigate wave-form, propagation and irregular beating; (2) neural activity assay based on three key measures: frequency of action potential firing, synchrony as measure for synaptic strength and oscillation as hallmark for neuronal organization in time; (3) (iPSC-)vascular smooth muscle contractility assay based on impedance alterations.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Kooy Frank
• Co-promoter: Labro Alain
• Co-promoter: Ponsaerts Peter
• Co-promoter: Rademakers Rosa
• Co-promoter: Snyders Dirk
• Co-promoter: Timmerman Vincent
• Co-promoter: Weckhuysen Sarah

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Neurodevelopmental disorders (NDD) are disorders which affect learning ability. Since genetic defects in many genes are linked to NDD's, diagnosis and treatment are difficult. Moreover, for the majority of NDD patients, the genetic cause remains unknown. However, there is growing evidence that for different NDDs a common molecular pathway is affected. For example, there is an enrichment of genes involved in chromatin remodelling. Disorders caused by mutations in genes regulating chromatin remodelling are called chromatinopathies. In this project, we want to study five distinct chromatinopathies: Kabuki, Kleefstra, Gabriele-de Vries, Helsmoortel-Van der Aa and a syndromic type of autism caused by mutations in KMT2D, EHMT1, YY1, ADNP and CHD8 respectively. The rationale for studying these five disorders is that the corresponding genes are involved in shared biological processes and that they have overlapping clinical features. We thus hypothesize that mutations in these five genes give rise to unique as well as common downstream effects in gene transcription and translation.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Vandeweyer Geert
• Fellow: Van Rossem Kirsten

Research team(s)

• Medical Genetics (MEDGEN)

Project website

Project type(s)

• Research Project

Abstract

Despite the unprecedented number of recent novel disease gene identifications in neurodevelopmental disorders such as intellectual disability, autism, or schizophrenia, our understanding of the pathogenicity mechanisms and associated clinical spectra are limited. We are an existing, established and productive ERA-NET neuron consortium. In our ongoing network, we studied mutations in ADNP, originally identified as a gene involved in syndromic autism, using a suite of cellular and animal models and tools developed. Since our results obtained in the ongoing project indicated a much broader clinical phenotype than anticipated and linking ADNP to multiple dimensions of epigenetic regulation, we now propose to apply our resources to investigate the involvement of the epigenome in the phenotypical presentation of mental disorders, using ADNP as a model. Our work will be based on the materials we generated in the ongoing application, including unique cellular and specifically for this project created animal models of the disorder. The work plan consists of six work packages, including disease characterization in patients and animal models, transcriptomics and epigenomics, functional analysis, mosaicism analysis, data integration and preclinical drug testing. These results will enable a full characterization of the consequences of the ADNP mutation that can be linked to the specific aspects of the diseases caused by ADNP mutations.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

• Medical Genetics (MEDGEN)

Project website

Project type(s)

• Research Project

Abstract

With this work, we want to add evidence to our hypothesis that expanded CGG-repeats in the genome can explain a percentage of the genetic causes of patients with a the mental handicap. Disorders caused by repeat expansions remain hidden from routine diagnostics at the moment due to the inherent limitations of the commonly used short read sequencing technologies. These are not able to detect repeat expansions. Yet, repeat expansions is the cause of the fragile X syndrome, the most frequent cause of ID and we argue in this proposal that many more repeat expansions in the genome may underlie as yet unknown forms of ID. In this proposal, we aim to specifically look for novel repeat expansion disorders in a population of a yet undiagnosed patients.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Neurodevelopmental disorders (NDDs) represent a large and heterogeneous group of rare disorders. Individual types of NDDs with a known genetic etiology are typically rare, owing to the very high number of individual genes that are causative for such conditions, but their aggregate societal impact is dramatic. Among the causative mutated genes, most are involved in two broad functional domains, synaptic processes and chromatin regulation ("epigenetic mechanisms"). In this proposal we selected five distinct NDDs: Kabuki, Kleefstra, Gabriele-de Vries, Helsmoortel-Van der Aa, and a syndromic type of Autism Spectrum Disorder (ASD) caused, respectively, by mutations in KMT2D, EHMT1, YY1, ADNP and CHD8. The uniquely informative edge of jointly studying these specific NDDs stems from the involvement of the causative genes in inter-related chromatin pathways, both directly and through their associated protein partners, and from the observation of major overlapping clinical features. We thus hypothesize that mutations in these five genes give rise to major transcriptional dysregulation in both common as well as unique gene regulatory networks, thereby generating shared and unique downstream effects in gene transcription and translation. Therefore, the IMPACT collaborative project aims to reveal common molecular and cellular signatures of chromatinopathy gene disruptions. Such converging mechanisms of disease offer an attractive target for the development of knowledge-based therapeutic interventions across individual NDDs that can potentially be useful for designing interventions suitable for multiple related rare neurodevelopmental disorders.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Vandeweyer Geert

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Physical and functional interactions between biomolecules play pivotal roles in all aspects of human health and disease. Gaining a greater understanding of these biomolecular interactions will further expand our understanding of diseases such as cancer, metabolic diseases and neurodegeneration. At UAntwerp, 7 research groups have joined forces to obtain the absolutely necessary equipment to measure these interactions with a Biomolecular Interactions Platform (BIP). This will allow to detect interactions and precisely determine binding affinities between any kind of molecule, from ions and small molecules to high-molecular weight and multi-protein complexes. The BIP will also allow to identify collateral off- targets, crucial in the drug discovery field. Access to a BIP will strongly support ongoing research projects and bring research within the BIP-consortium to a higher level. Since biomolecular interactions are highly influenced by the methodology, it is recommended to measure the interaction by several, independent techniques and continue with the most appropriate one. For this reason, the consortium aims at installing a BIP, consisting of several complementary instruments that each measure biomolecular interactions based on different physical principles. They wish to expand the existing Isothermal Titration Calorimetry with two complementary state-of-the- art techniques: MicroScale Thermophoresis and Grating- Coupled waveguide Interferometry.

Researcher(s)

• Promoter: De Meester Ingrid
• Co-promoter: Delputte Peter
• Co-promoter: De Wael Karolien
• Co-promoter: Dewilde Sylvia
• Co-promoter: De Winter Hans
• Co-promoter: Kooy Frank
• Co-promoter: Lambeir Anne-Marie
• Co-promoter: Maudsley Stuart
• Co-promoter: Van Der Veken Pieter
• Co-promoter: Van Ostade Xaveer

Research team(s)

• Medical Biochemistry

Project type(s)

• Research Project

Abstract

While the introduction of next generation sequencing led to a breakthrough in the discovery of novel genes responsible for neurodevelopmental disorders, most notably intellectual disability and autism, our understanding of the underlying disease causing pathology is lagging behind, in part due to the extreme genetic heterogeneity. Despite substantial in silico evidence that many diseases genes responsible for neurodevelopmental disorders cluster in a relatively limited number of protein protein interaction (PPI) networks, no experimental work on the subtle phenotypical effects that disturbances of such a network may cause has been reported to our knowledge. In this application, we therefore zoom in for the first time on the effects of the combined genetic variation present in an entire PPI network, rather than on the effect of mutations in single genes. We selected the AnkyrinG interactome, as it is a well-defined interaction network that is strongly connected with multiple neurodevelopmental disorders. By a detailed characterization of the genetic variation present in the AnkyrinG interactome in a large patient cohort, in combination with transcriptomics, proteomics and validation studies, we want to define the role of this PPI network as a unifying factor in neurodevelopmental disorders.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Vandeweyer Geert

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Clinical trials in the fragile X syndrome patients, a frequent form of intellectual disability, have been initiated based upon involvement in a number of pathways. What we have learned so far is that we are only in part able to determine the outcome of the trial, due to a lack of easily measurable outcome measures. Over the last years, evidence accumulated that the phosphorylation of specific proteins is altered in the blood of fragile X syndrome patients. Some of the phosphorylation abnormalities that have been detected cluster in the glutamatergic and the GABAergic pathway, the two pathways that have been already been explored for targeted treatment in patients fragile X syndrome. In this project, we propose to measure the phosphorylation abnormities of more than 144 peptides at once, using a novel array-based technology developed by a company called PamGene. We hope that these phosphorylation abnormalities can be potentially used to monitor the effect of a future clinical trial.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Today, technologies exist that are able to screen complete human genomes for genetic defects, hereby producing massive amounts of data. These techniques include microarrays for the detection of duplicated or missing genomic material and next-generation sequencing for the detection of variation at the nucleotide level. In parallel, extensive public resources contain additional biological information on the observed variation to aid in interpretation of the data. While some variants show full penetrance, others can be present in both seemingly healthy and severely impaired family members, indicating that disease modifying variants play a role in the clinical presentation. This led to the formulation of a 'many genes, common pathways' paradigm. To study genetic variation under this paradigm, novel models placing interpretation of individual results in a context of multiple patients are mandatory. Searching for common patterns over large patient cohorts might identify recurrently affected pathways with a critical role in the studied disease. Simultaneously considering multiple variants affecting such a pathway will thus help to explain both the observed phenotype and combined with pedigree information, the intrafamilial variability. Here, we will investigate how we can apply state-of-the-art data mining methods to reveal hidden relationships between variants, with the goal of gaining new insights in the molecular pathology of heritable diseases, focusing on cognitive disorders.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Laukens Kris
• Fellow: Vandeweyer Geert

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Clinical trials in the fragile X syndrome patients, a frequent form of intellectual disability, have been initiated based upon involvement in a number of pathways. What we have learned so far is that we are only in part able to determine the outcome of the trial, due to a lack of easily measurable outcome measures. Over the last years, evidence accumulated that the phosphorylation of specific proteins is altered in the blood of fragile X syndrome patients. Some of the phosphorylation abnormalities that have been detected cluster in the glutamatergic and the GABAergic pathway, the two pathways that have been already been explored for targeted treatment in patients fragile X syndrome. In this project, we propose to measure the phosphorylation abnormities of more than 144 peptides at once, using a novel array-based technology developed by a company called PamGene. We hope that these phosphorylation abnormalities can be potentially used to monitor the effect of a future clinical trial.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Fragile X syndrome is the most common form of inherited intellectual disability and autism. It is also one of the most frequent hereditary diseases. Over the last decades, this condition has become an example as model for a developmental neurological disorder, where by means of the study of the molecular mechanisms of the disease therapeutic targets have been discovered, which are currently being tested in clinical trials. Traditionally, the Benelux is the centre of fragile X research in Europe. The WOG unites these groups and aims to be a platform for translational research in the fragile X syndrome.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Autism, perhaps best characterized by a lack of social skills, is a poorly understood disorder. We know little about the different types of the disorder. Though is clear that genetics plays an important role in the occurrence of the disorder, of very few forms of autism the cause is known. In this project, we will study a form of autism that is caused by mutations in a single gene called ADNP. Mutations in this gene lead to autism in almost all patients known to date. Using an established mouse model of Adnp-autism, which mimics the disorder allows us to study the disorder in vivo, and to test drugs for possible later use in humans. It is known that a specific part of the ADNP protein called NAP can replace many of the functions of the entire protein, thereby indicating that NAP can be a primary drug candidate for testing in the Adnp-autism mouse model. In addition, as we know little of the consequences of the mutation in human cells, we will produce neuron-specific cell types generated from patient-derived skin biopsies, using the technique of induced-pluripotent stem cells. Thus, we will be able to study the processes that are disturbed in patient brain cells. By applying a variety of state of the art technologies, our network will detect novel pathways in cells disturbed in ADNP, and in related forms of autism. Once we characterized those pathways, we can then try to modify them for clinical benefit, using novel drugs. Finally, since many unrelated patients share the very same ADNP mutation, we will determine the mechanism of how these mutations arise. Knowledge of the mutational mechanism may be another way of detecting or preventing the disease in the future.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Vandeweyer Geert

Research team(s)

Project type(s)

• Research Project

Abstract

Despite substantial in silico evidence that many diseases genes responsible for neurodevelopmental disorders cluster in a relatively limited number of protein protein interaction (PPI) networks, no experimental work on the subtle phenotypical effects that disturbances of such a network may cause has been reported to our knowledge. In this application, we therefore zoom in for the first time on the effects of the combined genetic variation present in an entire PPI network, rather than on the effect of mutations in single genes. We selected the AnkyrinG interactome, as it is a well-defined interaction network that is strongly connected with multiple neurodevelopmental disorders. By a detailed characterization of the genetic variation present in the AnkyrinG interactome in a large patient cohort, in combination with transcriptomics, proteomics and validation studies in animal models, we want to define the role of this PPI network as a unifying factor in neurodevelopmental disorders.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Vandeweyer Geert
• Fellow: Cappuyns Elisa

Research team(s)

Project website

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

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Kooy Frank
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Ostade Xaveer

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

The main objective of this study is to increase our insights into how variation in ANK3 leads to a variety of neurodevelopmental manifestations. Mutations in ANK3 were recently described by our group to cause autism, ADHD and cognitive deficits in one patient and intellectual disability and behavioral problems in other patients. In other studies, ANK3 was linked to schizophrenia and bipolar disorder. This study will ultimately lead to a better understanding of the molecular interconnection of autism spectrum disorders, intellectual disability, ADHD and other neurodevelopmental disorders.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: van der Werf Ilse

Research team(s)

Project type(s)

• Research Project

Abstract

Enhancement of the function of the GABAA receptors may have major therapeutic benefits for fragile X syndrome. Previous studies have highlighted the synthetic neuroactive steroid analog ganaxolone as a possible therapeutic agent. We will determine whether ganaxolone is safe and effective to treat behavioural problems in fragile X syndrome with a focus on anxiety and attention deficits. We will use a variety of weil validated assessment batteries as outcome measures. The tests will be carried out after a 6-week treatment period.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

In this project, we will investigate how we can apply state-of-the-art data mining methods to reveal hidden relationships between variants, with the goal of gaining new insights in the molecular pathology of heritable diseases, focusing on cognitive and cardiac disorders.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Laukens Kris
• Co-promoter: Loeys Bart
• Co-promoter: Van den Bulcke Tim
• Fellow: Vandeweyer Geert

Research team(s)

Project type(s)

• Research Project

Abstract

The human genome project has led to the identification of all base pairs in the human genome. Moreover, technological breakthroughs have led to the development of equipment that enables laboratories of our size to sequence all coding exons of an individual in a single run. Intellectual disability occurs in 2-3% of the world population. This means that in Flanders alone between 120.000 en 180.000 persons are affected. In maximally half of patients a diagnosis is made. This implies that no specialized treatment is possible for these patients and no estimation of the recurrence risk can be provided to their families. By implementing the latest technology in our laboratory we want to identify a number of novel mental retardation disorders. We plan to accomplish this by sequencing the exome (= sequence of all coding basepairs in the genome) of patients with a mental handicap and compare their exomes with those of their parents. This way, we can discover de novo mutations in genes that are causative for the mental handicap in these patients. We will study the function of these genes by obtaining and studying animal models of these genes.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Helsmoortel Céline

Research team(s)

Project type(s)

• Research Project

Abstract

CNV-WebStore is a software package that allows the annotation and storage of genomic copy number variation in an intuitive way. At present, we are using this program for the in house analysis of our CNV data, both in research and in a clinical setting. With this application, we aim to build in additional features in the program and also plan to professionalize the program in order to use it for commercial purposes.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Rooms Liesbeth

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we want to demonstrate that correction of the GABAergic system in an animal model can ameliorate the symptoms of the fragiIe X syndrome. To this end, we will generate a genetic rescue mouse of the disorder and analyze a multitude of aspects of its phenotype.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

In this project we want to study whether a correction of the GABAergic system can ameliorate the clinical symptoms of fragile X syndrome in animal models. In the first part of the project we will analyze the effects of a genetic correction of the deficiënt GABA synthesis in the fragile X mouse. In the second part of the project, the therapeutic efficiency of drugs that specifically target the GABAA receptor will be evaluated.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Braat Sien

Research team(s)

Project type(s)

• Research Project

Abstract

With this project we want to increase our insights in the role of dynamic mutations in mental retardation. By means of molecular techniques (MS-MLPA, MSP, array-MLPA) we will identify new rare fragile places off CGG-repeats in the human genome and characterise the underlying genes. Selected genes who's involvement in mental retardation in humans seems most probable, are subjected to a detailed functional characterisation, among other things by use of animal models.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Metsu Sofie

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project type(s)

• Research Project

Abstract

Despite recent progress in the understanding of fragile X syndrome, there is no targeted treatment for this disease. In previous studies we showed that the amount of GABA(A) receptors is significantly decreased in fragile X animal models and that this receptor is a suitable target for treatment. However, before drugs can be tested on human patients, the abnormalities of the GABAergic system observed in animal models need to be verified in human patients. Therefore, we propose to perform position emission tomography (PET), a functional imaging technology that is able to provide non-invasive in vivo assessment and quantification of GABAA receptor binding through injections of labelled flumazenil. A difference in GABAA receptor distribution between fragile X patients and controls will enforce our hypothesis that a dysfunction of the GABAergic system is responsible for the neurologic and behavioural problems seen in fragile X patients. Our research will thus strongly encourage drug trials on fragile X patients.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

The principal objective of the proposed study is to understand the mechanisms behind the neuropathology of fragile X syndrome using a knockout mouse model for the syndrome. In particular we aim to investigate the cellular and molecular mechanisms behind the reduced expression of the different components of the GABAergic system in fragile X syndrome. The outcome will provide a possible base for rational drug treatment of the fragile X syndrome.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project type(s)

• Research Project

Abstract

We want to test the hypothesis whether the GABAergic system might be a target for treatment of fragile X syndrome. We will construct a genetic rescue mouse model to verify whether correction of deficient GABA synthesis rescues the fragile X phenotype in knockout mice.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Rooms Liesbeth

Research team(s)

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Van der Aa Nathalie

Research team(s)

Project type(s)

• Research Project

Abstract

Fragile X syndrome is the most common form of inherited mental retardation, with an incidence of 1:2500. Despite the fact that FMR1, the gene inactivated in patients, was cloned in 1991, little is known about the role of the FMR1 protein, FMRP in the pathophysiology of the disorder and treatment is symptomatic.Over the last years, we and others have clearly demonstrated a deficiency of the GABAergic system in fragile X syndrome animal models. The GABAergic system is the main inhibitory system in the brain. A decreased deficiency of the GABAergic system is in line with the clinical symptoms observed in patients, including hyperactivity, anxiety and epilepsy. Interestingly, numerous drugs of clinical importance that act on the GABA(A) receptor are on the market and even more are in the various stages of development. The GABAergic system is thus an attractive target for rational drug treatment in the fragile X syndrome.Before any drug trials can be initiated, however, our observations from animal models need to be validated in human subjects. As autopsy material of fragile X patients is not readily available, we propose to measure the amount of GABA(A) receptor in fragile X patients using Positron Emission Tomography (PET) with [11C]flumazenil. We will image and quantify the differences in GABA(A) receptor distribution between ten fragile X patients and ten controls.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

With this project we want to increase our insights in the role of dynamic mutations in mental retardation. By means of molecular techniques (MS-MLPA, MSP, array-MLPA) we will identify new rare fragile places off CGG-repeats in the human genome and characterise the underlying genes. Selected genes who's involvement in mental retardation in humans seems most probable, are subjected to a detailed functional characterisation, among other things by use of animal models.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Metsu Sofie

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to develop an automatic detection method to diagnose cytogenetically invisible chromosome abnormalities in patients with a mental handicap. In order to do so, we will use array-based MLPA (Multiplex Ligation-dependent probe Amplification). This will ultimately lead to an increased detection percentage in this group of patients, resulting in a better prognosis for the patients and an improved estimation of the recurrence risk in the family.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Rooms Liesbeth

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

This project aims to detect novel genome disorders in mental retardation by performing SNP arrays on a series of selected patients with a mental handicap. It can be anticipated that novel deletions will be discovered. The size of the deletions will be determined and analysis of breakpoints will increase our insights in the mechanisms causing the rearrangements. Candidate genes in the deletions will be identified and analyzed using mouse models.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Ceulemans Berten

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

We want to develop an array-based MLPA (multiplex-ligation dependent probe amplification) method for the detection of microdeletions and duplications amongst the mentally retarded. At present, no single method is able to detect all interstitial and subtelomeric deletion/duplications simultaneously. Our aim is to develop a test that can detect all known micredeletion syndromes in a single reaction on a novel array platform. Thiq project will contribute to the development of a diagnostic test that will eventually replace conventional karyotyping.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Fragile X syndrome is the most common form of mental retardation. Apart from mental retardation, patients suffer from behavioral problems, such as hyperactivity and communicational difficulties, epilepsy and anxiety. In everyday life, the behavioral problems can be as much as a burden for the parents as the mental impairment. We have discovered in animal models that in fragile X syndrome the GABA receptor, a molecule in our brain that is responsible for the inhibition of neurotransmission, is underexpressed. In other words, fragile X patients are expected to have les inhibitory receptors in their brain. This is compatible with the symptoms observed in fragile X patients, e.g. the hyperactivity, anxiety and epilepsy and potentially also with the learning difficulties. As numerous drugs of clinical importance that bind to the GABA receptor are on the market, we want to test in animal models whether these drugs that work on the GABA system might be suitable drugs for treatment of the behavioral problems and the epilepsy in the fragile X syndrome

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

The aim of this study is to develop an array-based multiplex ligation-dependent amplification (MLPA) method to detect microdeletions and microduplications in the mentally handicapped. The test needs to be rapid and unequivocal. To archive our goal, we will use 4-MAT technology that will allow us to simultaneously detect all known interstitial and subtelomeric loci involved in mental retardation in a large number patient population.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Rooms Liesbeth

Research team(s)

Project type(s)

• Research Project

Abstract

Fragile X syndrome is the most common form of mental retardation. Apart from mental retardation, patients suffer from behavioral problems, such as hyperactivity and communicational difficulties, epilepsy and anxiety. In everyday life, the behavioral problems can be as much as a burden for the parents as the mental impairment. We have discovered in animal models that in fragile X syndrome the GABA receptor, a molecule in our brain that is responsible for the inhibition of neurotransmission, is underexpressed. In other words, fragile X patients are expected to have les inhibitory receptors in their brain. This is compatible with the symptoms observed in fragile X patients, e.g. the hyperactivity, anxiety and epilepsy and potentially also with the learning difficulties. As numerous drugs of clinical importance that bind to the GABA receptor are on the market, we want to test in animal models whether these drugs that work on the GABA system might be suitable drugs for treatment of the behavioral problems and the epilepsy in the fragile X syndrome.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project type(s)

• Research Project

Abstract

Recently, we found differential expression of the delta subunit of the -aminobutyric acid type A (GABAA) receptor in the brain of the fragile X knockout mouse, an animal model for the most frequent form of familial mental retardation. GABAA receptors have been implicated in anxiety, epilepsy, and learning and memory and numerous drugs of clinical importance bind to receptor. The purpose of this project is to increase our insights in the role the GABAA receptor in the fragile X syndrome using a variety of molecular techniques.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project type(s)

• Research Project

Abstract

Recently, we found differential expression of the delta subunit of the ?-aminobutyric acid type A (GABAA) receptor in the brain of the fragile X knockout mouse, an animal model for the most frequent form of familial mental retardation. GABAA receptors have been implicated in anxiety, epilepsy, and learning and memory and numerous drugs of clinical importance bind to receptor. The purpose of this project is to increase our insights in the role the GABAA receptor in the fragile X syndrome using a variety of molecular techniques.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

In contrast to severe mental retardation that is usually caused by defects in a single gene, mild mental retardation is caused by a multitude of genetic factors or QTLs. This project aims to aims to identify one QTL responsible for mild mental retardation in a mouse model. A 'dull' and a 'bright' colony will be bred starting from a single colony of outbred HS mice by repeated backcrossing while selecting for extreme learning performance. Genetic mapping will subsequently be used to identify the QTL.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: De Deyn Peter

Research team(s)

Project type(s)

• Research Project

Abstract

Mental retardation, with an estimated frequency of 1-3% in the population, is in 50% of the cases due to a genetic defect. Subtelomeric rearrangements are responsible for 5-10% of all cases of idiopathic mental retardation. These subtelomeric regions are gene rich and often involved in chromosomal rearrangements. Aim of the project is to increase our insights in the importance of these rearrangements by screening patients with idiopathic mental retardation and by identifying the deleted genes. In addition we will develop a novel faster diagnostic method to screen for these rearrangements.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project type(s)

• Research Project

Abstract

Evidence has accumulated that a number of modifier genes in addition to the disease causing mutation determine the severity of fragile X syndrome, the most frequent form of inherited mental retardation. We propose to identify these modifiers by analyzing the progeny of carefully structured crosses between the fragile X knockout mouse and a genetically heterogeneous stock in the Morris water maze. Comparison of the analysis of a set of polymorphic markers evenly distributed throughout the genome will enable us to localize the modifier genes.

Researcher(s)

• Promoter: Kooy Frank

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

Mental retardation, with an estimated frequency of 1-3% of the population, is in 50% of cases due to a genetic defect. Aim of the current project is to increase our insights in the factors that cause mental retardation in patients. This will be archived by identifying and analyzing genes that cause mental retardation in families with mental retardation of an unknown cause, as well as by inventarizing factors that influence the fragile X gene. The latter implies that genes that influence the cognitive capacities of fragile X patients, as well as genes whose expression is influenced by absence of the fragile X gene will be identified and characterized (in the fragile X mouse model).

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project type(s)

• Research Project

Abstract

Mental retardation occurs in about 1-3% of the total population. It has an unrivalled impact on the lives of the patient and his close relatives. In an estimated 50% of cases, the mental handicap is due to genetic defects. However, in half of cases, the cause of the mental handicap remains unknown. This implies ao that no genetic advice about the recurrence risk can be given to the parents or their relatives. Recently, it was described that certain subtle rearrangements of the telomeres of the chromosomes could be a frequent cause of mental retardation. Such abnormalities, that were thus far never noticed, could be responsible for up to 10% of cases of mental retardation. By screening 100 patients with mental retardation for the presence of these subtelomeric rearrangements, we will be able to determine the relevance of these 'novel' abnormalities in the Antwerp population of mentally handicapped.

Researcher(s)

• Promoter: Kooy Frank

Research team(s)

Project type(s)

• Research Project

Abstract

The fragile X knockout mouse is valuable model to study the molecular abnormalities in the fragile X syndrome. Purpose of the proposed research is to analyze whether the phenotype of the knockout mouse can be restored by introduction of an FMR1 transgene in the germ line. Rescue of the phenotype could demonstrate that fragile X syndrome, at least in the mouse model, is a potentially correctable disorder, a result that might have significant diagnostic implications.

Researcher(s)

• Promoter: Kooy Frank

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 studied by constructing a knockout mouse model.

Researcher(s)

• Promoter: Kooy Frank
• Fellow: Winnepenninckx Birgitta

Research team(s)

Project type(s)

• Research Project