Research Wim Wuyts

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. The molecular basis of peripheral chondrosarcoma development is are currently unknown. This leads to the lack of prognostic markers and, most importantly, the absence of a therapeutic approach alternative to the surgery. This project aims the identification of pathways underlying peripheral chondrosarcoma development and identify prognostic markers in patients with mutiple osteochondroma (MO), who are at increased risk of developing peripheral chondrosarcoma.

Researcher(s)

• Promoter: Wuyts Wim

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: Wuyts Wim
• Fellow: Jennes Ivy

Research team(s)

Project type(s)

• Research Project

Abstract

Maturity-Onset-Diabetes-of-the Young (MODY) is a monogenic, genetic heterogeneous form of diabetes which is characterized by autosomal dominant inheritance and early onset. This project aims the development of a fast detection method for the detection of deletions in the most frequently mutated MODY genes; the glucokinase (MODY2) and HNF1a (MODY3) genes. This should lead to a better, more sensitive molecular diagnostics for MODY patients.

Researcher(s)

• Promoter: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

European network to promote research into uncommon cancers in adults and children: Pathology, Biology and Genetics of Bone Tumors. (EuroBoNet) Primary bone tumours are rare, accounting ~0.2% of the cancer burden. Children and young adolescents are frequently affected. Their aggressiveness has major impact on morbidity and mortality. Though progress has been made in pathological and genetic typing, the aetiology is largely unknown. Though advances in therapeutic approaches increased survival, significant numbers of patients (~40%) still die. Within the EuroBoNeT integration will be achieved by staff exchange and website-based discussion forums to increase and disseminate knowledge of primary bone tumours at the molecular level for development of new tools for patient care and cure and technology. With this integration exchange of material (virtual BioBank), Standard Operating Protocols and the use of technology platforms will enable us to obtain statistical significant datasets, otherwise not achievable due to the rareness and large number of sub entities. A joint programme will contribute in obtaining molecular portraits of tumours, separated in 4 research lines (RL). In each RL the biology of the separate group (RL1: cartilaginous tumours; RL2: osteogenic tumours and related sarcomas; RL3: osteoclastogenesis and Giant cell tumours of bone; and RL4: Ewing family of tumours) will be examined by genome wide expression and genomic aberration studies. More specific hypothesis driven approaches will be investigated by RNA/protein expression and mutation analysis. Knowledge on normal growth and differentiation will be gathered through in vitro studies. This would lead to further understanding and identification of markers for malignant transformation and/or progression, as well as identification of therapeutic targets. Next to research, dissemination of knowledge will be achieved by training courses on bone and soft tissue pathology for all interested. The last is required since patients usually do not present themselves at centres, which necessitates spreading of knowledge.

Researcher(s)

• Promoter: Wuyts Wim
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Previous studies have shown that the majority of patients suffering from Multiple hereditary osteochondroma (MHO/MHE) harbor an EXT1 or EXT2 mutation. However, a significant fraction of patients does not show a mutation due to the different mutation detection techniques used in the various studies and because most labs do not invest in laborious and expensive techniques to identify mutations which are not found by standard mutation analysis of EXT1 and EXT2. To identify a potential EXT1 or EXT2 mutation, these negative patients will be analyzed with the most sensitive techniques, including RNA and promotor analysis to identify intronic or regulatory mutations. The identification of mutations in regulatory regions may point to sequences crucial for proper EXT regulation and these sequences can be used as targets for the identification of proteins regulating EXT expression. In addition, linkage analysis will be performed in large families without an EXT1 or EXT2 mutation to investigate whether additional MHO causing genes do exist. At present it is not clear whether a phenotype-genotype correlation exist in MHO. This is mainly due to the low number of available samples in previous studies and to the lack of a uniform phenotype scoring system. With the construction of a large MHO network these two problems have been addressed and by pooling the samples of MHO patients which are contributed by the different partners of this collaboration, a significant number of patients is now available. Moreover all these patients will be genotyped according to the same mutation analysis SOP which guaranties optimal molecular analysis and they will be phenotypically scored by a uniform scoring system. This will result in a statistical power allowing to address the question whether and/or which genotype/phenotype correlation exists. MHO shows great clinical variability, even intrafamilial. This suggest that other genes influence the severity of this disease. To identify such potential modifiers, SNPs of various candidate genes, selected based upon their functional relevance in bone and cartilage development, will be analyzed in a large set of MHO patients to investigate association with certain genotypes and severity. Large MHO families will greatly increase the power of this analysis.

Researcher(s)

• Promoter: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims the functional analysis of the EXTL1 gene. By mutation analysis of this gene in different types of tumours its putative tumour suppressor capacity will be checked. Besides this we will try to elucidate the function of this gene and its protein by expression studies, the construction of a knockout mouse etc.

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Wuyts Wim
• Fellow: Mathysen Danny

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this study is the molecular and functional analysis of genes involved in bone formation and remodeling identified by positional cloning in hereditary bone disorders. The specific objectives of this project are twofold. The first part aims the identification of genes responsible for Paget's disease of bone (PDB), a frequent bone disorder affecting up to 5% of the population above 55 in the western world. The second part involves the functional analysis of genes involved in skull development. Paget's disease of bone (PDB) is characterized by increased bone resorption with a subsequent increased formation of poorly organized bone.To identify additional genes which can cause PDB, we are currently performing a genome wide screen in a large Spanish and American PDB family. Once a localization for the PDB causing gene in these families will be obtained, additional polymorphic markers will be analyzed to reduce the candidate region and genes and new transcripts from the candidate regions will be screened to identify the PBD causing mutation. Functional analysis of the PDB causing genes will then reveal the exact mechanism underlying this disease In a second part we will concentrate on the study of the ALX/MSX homeoboxgenes which where previously shown to be involved in skull development. To further characterize the exact function and regulation of the ALX4 gene we will isolate and identify flanking regulatory sequences by making deletion constructs of the ALX4 promotor region and analyzing the regulatory effects of these deletions by luciferase reporter gene assay. In addition the mouse Alx4 promotor will be characterized to identify potential conserved regulatory sequences. Additionally, further isolation, detailed physical mapping and functional characterization of potential new members of these gene families may elucidate their exact function and may reveal whether mutations in these genes also lead to defects in skull development.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The MSX gene family is a family of homeobox genes involved in embryonic development of several species. In humans, two MSX gen es (MSX1 and MSX2), have already been characterized, while in mice three Msx gen es (Msx1-3) have been isolated. This project aims the isolation and functional characterization of the human MSX3 gene and additional human members of this gene family to reveal the function of these genes and their possible involvement in human disorders .

Researcher(s)

• Promoter: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The EXT/EXTL gene family is a family of putative tumour suppressor genes which comprises at present 5 genes, including 2 EXT genes and 3 EXT -like (EXTL) genes. Both EXTl and EXT2 genes have been shown to play a role in heparan sulfate (HS) biosynthesis, where they are involved in HS polymerization. Also EXTL2 is involved in the same HS pathway as it was identified as the critical enzyme that initiates HS biosynthesis and separates it from the chondroitin/dermatan sulfate biosynthesis. EXTL3 was shown to be a receptor for reg (regenerating gene) protein, a pancreatic beta-cell regeneration factor while for the EXTL 1 gene no function has been determined yet. At present no disease has been associated with EXTL 1, but its homology to the EXT tumour suppressor genes and its localization in the 1 p36 tumor suppressor region makes it a serious candidate for the tumours associated with this region. This project aims the construction and analysis ofan EXTLl knock-out mouse. A vector containing an inactivated copy of the EXTL 1 gene will be constructed and electroporated in ES cells. If homologous recombination between the mutant construct and wild type EXTLl has occurred, mice blastocysts will be injected with these ES cells to obtain chimeric mice. These chimeric mice will then further be breeded to obtain mice carrying one and two inactive copies of the EXTL 1 gene. Both homozygous and heterozygous EXTL 1 mutant mice will be studied extensively to identify potential phenotypic abnormalities associated with EXTL 1 mutations. At present no EXTL 1 mutations have been described in humans, and therefore one can not predict the phenotype in mice carrying an EXTLl mutation. However, as EXTLl shows homology to the EXT genes analysis of the skeletal structures by X-rays and analysis of the heparan sulfate composition by HPLC will be given high priority.

Researcher(s)

• Promoter: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims at the localisation and identification of genes predisposing to Paget's disease by performing genetic linkage studies in families.

Researcher(s)

• Promoter: Dumon Jan
• Fellow: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The fragile X syndrome is caused by amplification of a repeat in the fragile X gene (FMR1). The function of FMR1 and the mechanism of amplification are unknown. Both will be studied by the analysis of transgenic mice with a FMR1 knockout mutation or oocyt injection of FMR1 constructs with repeat amplification.

Researcher(s)

• Promoter: Willems Patrick
• Fellow: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The fragile X syndrome is caused by amplification of a repeat in the fragile X gene (FMR1). The function of FMR1 and the mechanism of amplification are unknown. Both will be studied by the analysis of transgenic mice with a FMR1 knockout mutation or oocyt injection of FMR1 constructs with repeat amplification.

Researcher(s)

• Promoter: Willems Patrick
• Fellow: Wuyts Wim

Research team(s)

Project type(s)

• Research Project