Ongoing projects

Screening and early detection of colorectal cancer and breast cancer in liquid biopsies using a newly-developed multi-regional methylation assay. 01/11/2020 - 31/10/2022

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.

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Improving current cancer detection and treatment follow-up through the development of a next generation cancer assay. 01/02/2020 - 31/01/2022

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.

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Improving current cancer detection and treatment follow up through the development of next generation cancer assays. 01/01/2020 - 31/12/2023

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.

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Research team(s)

Leveraging patient-driven research to improve rational therapy selection in (ROS1+) non-small cell lung cancer. 01/01/2020 - 31/12/2021

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.

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Identification of pan-cancer and tumor-specific methylation based biomarkers and development of bioinformatics infrastructure for a novel multiplex methylation assay. 01/11/2019 - 31/10/2021

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.

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Past projects

Development of a multi-region methylation blood based test for pan-cancer detection. 01/11/2019 - 30/10/2020

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.

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Tissue engineering for conjunctival reconstruction: Introducing self-assembled collagen-like-peptide scaffolds for the expansion of human conjunctival-derived cells in a xeno-free and serum-free environment. 01/10/2017 - 30/09/2019

Abstract

English Title: Tissue engineering for conjunctival reconstruction: Introducing self-assembled collagen-like-peptide scaffolds for the expansion of human conjunctival-derived cells in a xeno-free and serum-free environment. The human eye is a unique, biological complex but vulnerable entity. It lacks protection of keratinized epithelium against infection and desiccation, as seen in almost every other area of the body. However, the ocular surface is specialised to protect the ocular structures and respond rapidly upon injury, while maintaining a smooth refractive surface to ensure visual acuity. One of the specialised cellular layers contributing to ocular tissue homeostasis is the conjunctiva. This thin mucous membrane belongs to the ocular surface epithelia, covering the sclera and the inside of the eyelids. In some ocular disorders, the conjunctiva is damaged, resulting in extensive scarring and inflammation, which can lead to several pathological conditions such as eyelid distortions, tear film disruptions, severe dry eyes, corneal ulcers and eventually blindness. The management of severe conjunctival surface disorders remains challenging for ophthalmologists worldwide. The conventional treatment comprises the surgical excision of the diseased conjunctiva. Normal wound healing post resection is based on epithelial migration from adjacent healthy conjunctiva to the wounded area. However, this healing process cannot take place in patients lacking sufficient healthy residual conjunctiva. Here, fibrosis and scar formation will occur, often reintroducing several pathological conditions as described above. Hence to avoid sequelae, the ocular surface requires reconstruction post excision using a cellularized conjunctival substitute. In this project, we aim to meet this unmet medical need by creating a cellularized conjunctival substitute for reconstructive surgery. By introducing fully synthetic self-assembling collagen-like-peptide hydrogels as carrier for human conjunctival-derived cells and eliminating all animal-derived components, we aim to provide a safe, consistent and functional conjunctival replacement. The graft's functionality will be tested in vitro by means of specifically designed tests for presence of conjunctival epithelial cells (barrier formation against infectious microbes), mucin-producing goblet cells (tear film stabilization) and stem cells (epithelium renewal).

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Development of a biocompatible corneal endothelial cell based therapy to address global corneal donor shortage. 01/01/2016 - 31/12/2019

Abstract

Human corneal endothelial cells (HCEnC) regulate fluid and solute transport across the posterior surface of the human cornea and actively maintain the cornea in a dehydrated state, which is crucial for optical transparency.The dual function of the corneal endothelium is described as the "pump-leak hypothesis" which is essential to allow nutrition to the cornea whilst maintaining its avascularity and transparency. There is no evidence that human endothelial cells divide under normal circumstances as they are arrested in G1 phase of the cell cycle, although they can be induced to divide in vitro. When the amount of corneal endothelial cells decreases below a certain threshold, this cell layer can no longer pump sufficient fluid back to the anterior chamber, resulting in an irreversibly swollen, cloudy cornea. Despite its success, corneal transplantation (either full-thickness or partial) is limited worldwide by the shortage of suitable donor corneas incurring long waiting times. Initial progress to overcome this global shortage is the use of one donor cornea for multiple partial keratoplasties ("split-cornea transplantations"), by using one donor cornea for a partial endothelial and a stromal transplantation. This project aims to investigate ex vivo expansion of corneal endothelial cells to develop a cell sheet based therapy. This would overcome donor deficit that limits the treatment of corneal endotheliopathies. The principle is to expand primary human corneal endothelial cells isolated from human cadavers and to seed them on an ideal scaffolding material to introduce these cells in the patient. Specifically in this project we propose the expansion of human corneal endothelial cells (HCEnC) on human lens capsules to obtain a composite graft. The final goal of this project is a proof-of-principle of this functional cell sheet in a rabbit corneal endotheliopathy model.

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Elucidation of the molecular pathology of keratoconus and construction of a mouse model. 01/01/2014 - 31/12/2017

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.

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Unraveling the genetic etiology of sensory disorders: The role of calcium signaling genes at the auditory inner hair cell ribbon synapse and identification of new genes. 01/10/2013 - 07/07/2015

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.

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Identification and characterization of key players involved in calcium signaling at the auditory inner hair cell ribbon synapse. 01/01/2013 - 07/07/2015

Abstract

In the auditory system, a calcium influx-triggered exocytosis mediated by voltage-gated Cav1.3 (L-type) calcium channels in the cochlear inner hair cells (IHC) is necessary for the signal transduction of sound. One of the key regulators in this process are calcium binding proteins (CBPs), which antagonize calmodulin-mediated calcium dependent inactivation (CDI) of voltage-gated calcium channels. Recently, we identified a new gene, calcium binding protein 2 (CABP2), in which mutations cause moderate-to-severe hearing loss in three Iranian consanguineous families. In addition, another group recently identified a mutation in Cav1.3 (CACNA1D) that leads to congenital deafness and bradycardia in humans. These results clearly illustrate that Cav1.3 and CBPs are necessary for sound transmission in the human auditory system. Building upon these preliminary results, this project proposal focusses on screening of a large set of well-characterized patients with hearing loss for mutations in CABP2, other selected CBPs and CACNA1D to identify new mutations involved in hearing loss. Newly identified mutations will be characterized by an electrophysiological investigation to study their effect on Cav1.3 Ca2+ function and density. In addition, we will try to identify novel interaction partners for CACNA1D, CABP2 and selected CBPs to identify novel key players important in sound transmission at the ribbon synapse of the hair cells.

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Belgian medical genomics initiative (BeMGI). 01/04/2012 - 31/12/2017

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.

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Elucidation of the role of the apoptosis inducing DFNA5 protein via model systems in yeast, cell lines and the mouse. 01/01/2011 - 31/12/2014

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.

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Research team(s)

Identification of disease genes through next-generation sequencing 01/01/2011 - 31/12/2012

Abstract

Next-generation sequencing (NGS) is a revolutionizing technique for the identification of disease-causing genes. In this project, we attempt to identify the disease-causing mutation in 2 families with autosomal recessive forms of nonsyndromic deafness, in which a narrow candidate region has been delineated by linkage analysis. To obtain a successful gene identification, a thorough screening of these regions will be done using NGS techniques.

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Identification of genes for otosclerosis and elucidation of their role in the disease process. 01/10/2010 - 30/09/2013

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.

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Research team(s)

Methods for genetic epidemiological research into complex diseases based on dense SNP datasets.. 01/10/2010 - 30/04/2011

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.

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Development of a coated-wire potentiometric sensor for detection of DNA variants and mutations 01/07/2010 - 30/06/2014

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.

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Elucidation of the role of the apoptosis inducing DFNA5 protein via model systems in yeast, cell lines and the mouse. 01/01/2010 - 31/12/2013

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.

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Elucidation of the pathofysiology of DFNA5 - associated hearing loss. 01/01/2010 - 31/12/2011

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.

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DNA diagnostics for deafness using next generation DNA sequencing. 01/10/2009 - 30/09/2012

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.

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Genetic and functional studies for GRM7 and GRHL2, two genes for Age-Related Hearing Impairment. 01/10/2009 - 30/09/2011

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.

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Analysis of monogenic forms of deafness using dense genome-wide SNP data. 01/02/2009 - 31/12/2010

Abstract

The aim of this project is the identification of new loci for hereditary nonsyndromic forms of hearing loss. A unique collection of 30 highly informative Iranian families, with a high degree of consanguinity, is available. After an initial screening for recurrent mutations, a genome wide search is carried out using the most advanced techniques for genotyping using DNA chips, after which the diseases locus is pinpointed using linkage analysis.

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Identification and characterisation of genes responsible for age-related hearing impairment. 01/01/2009 - 31/12/2012

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.

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Research team(s)

Methods for genetic epidemiological research into complex diseases based on dense SNP datasets. 01/10/2008 - 30/09/2010

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)

Research team(s)

Identification of genes responsible for otosclerosis. 01/10/2008 - 30/09/2010

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.

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Research team(s)

Genetic and functional studies for GRHL2 and GRM7, two genes for Age-Related Hearing Impairment. 01/10/2008 - 30/09/2009

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.

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Research team(s)

Assessment of hearing in the elderly: aging and degeneration - integration through immediate intervention. 01/05/2008 - 30/04/2011

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.

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Identification of genes responsible for complex forms of hearing impairment using statistical and genetic-epidemiological techniques. 01/12/2007 - 30/11/2010

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.

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Linkage disequilibrium patterns, single nucleotide polymorphism-based analysis of population substructure and potential for genome-wide association studies in an isolated population. 01/10/2007 - 30/09/2008

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.

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Research team(s)

Identification and characterisation of genes responsible for hearing impairment. 01/01/2007 - 31/12/2010

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.

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Identification of genes for monogenic and multifactorial forms of otosclerosis. 01/01/2007 - 31/12/2008

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.

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Research team(s)

Identification of genes responsible for otosclerosis. 01/10/2006 - 30/09/2008

Abstract

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Research team(s)

Identification of genes responsible for nonsyndromic hearing impairment. 01/10/2006 - 30/09/2008

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.

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Identification of genes responsible for complex forms of hearing impairment using statistical and genetic-epidemiological techniques. 01/10/2006 - 31/03/2008

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.

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Research team(s)

Identification of susceptibility genes for complex types of hearing loss. 01/10/2006 - 31/03/2007

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.

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Discovery of genes correlated with occurence of prebycusis using DNA samples. 20/06/2006 - 20/12/2007

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.

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Identification of genes for complex forms of hearing impairment. 01/01/2006 - 31/12/2009

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.

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Identification of genes for noise-induced hearing loss. 01/01/2006 - 31/12/2008

Abstract

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Identification of modifier genes for hearing loss caused by GJB2 mutations. 01/05/2005 - 31/12/2006

Abstract

GJB2 mutations are responsible for a major part of prelingual hearing loss. The hearing loss ranges from mild to profound.The phenotypic variation can partially be explained by the GJB2 genotype. In addition to this genotype-phenotype correlation, modifier genes undoubtedly play a role in this variation. This project aims at the identification of these modifier genes using genetic association studies in carefully selected candidate genes.

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Construction and characterization of a mouse model for hereditary hearing impairment caused by mutations in DNA5. 01/01/2005 - 31/12/2007

Abstract

DFNA5 is a gene for an autosomal dominant, progressive, sensorineural hearing loss, starting at the high frequencies at an age of 5 to 15 years. A first attempt to generate a mouse model by mimicking the human mutation through targeted recombination resulted in a knockout mouse. However, the knockout mouse did not show any hearing loss. In the mean time, a hypothesis was formulated posing that the hearing loss probably was due to a gain-of-function and not, as was assumed before, to haplo-insufficiency. In this project the gain-of-function hypothesis will be further investigated, by the generation of a mouse model through pronuclear injection of human mutant DFNA5 cDNA coupled to the DFNA5 promoter.

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The study of KCNQ4, a hearing impairment gene. 01/01/2005 - 31/12/2006

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.

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Research team(s)

Identification of genes for monogenic and multifactorial forms of otosclerosis. 01/01/2005 - 31/12/2006

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.

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Research team(s)

Identification and characterisation of noise-induced hearing loss genes. 01/01/2005 - 31/12/2005

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.

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Advances in hearing science : from functional genomics to therapies. (EUROHEAR) 01/12/2004 - 30/11/2009

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.

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Identification of genes responsible for nonsyndromic hearing impairment and Meniere's disease. 01/10/2004 - 30/09/2006

Abstract

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Research team(s)

Etiological factors for age-related hearing impairment. 01/01/2004 - 31/12/2007

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).

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Construction and characterization of a transgenic mouse with a knockout in Coch, responsible for hearing loss and vestibular dysfunction in man. 01/01/2004 - 31/12/2007

Abstract

Mutations in the human COCH gene lead to autosomal dominant progressive hearing loss paralleled by vestibular dysfunction. To get a better understanding of the function of COCH and the way COCH mutations lead to inner ear dysfunction, we want to construct and chararacterize a transgenic mouse with a knockout of COCH.

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Identification of susceptibility genes for noise-induced hearing loss. 01/01/2004 - 31/12/2005

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).

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Study of monogenic and of complex forms of hearing impairment and vestibular dysfunction. 01/10/2003 - 30/09/2006

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)

Research team(s)

Identification of genes for monogenic and complex forms of otosclerosis. 01/10/2003 - 30/09/2004

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)

Research team(s)

Identification of environmental and genetic risk factors for age related hearing impairment (ARHI). 01/03/2003 - 31/05/2007

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)

Research team(s)

The study of KCNQ4, a hearing impairment gene. 01/01/2003 - 31/12/2004

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)

Research team(s)

Identification and characterization of genes responsible for two types of hereditary hearing impairment. 01/01/2003 - 31/12/2004

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)

Research team(s)

Otosclerosis - A Molecular Genetic Study. 01/05/2002 - 30/04/2007

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.

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Research team(s)

Identification of genes resposible for age-related hearing impairment. 01/04/2002 - 31/03/2005

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

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Research team(s)

Identification and characterisation of heritable monogenic and polygenic disorders. 01/01/2002 - 31/12/2006

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.

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Research team(s)

Identification and characterisation of genes for hearing impairment and vestibular dysfunction in ENU mouse mutants. 01/01/2002 - 31/12/2004

Abstract

To study the molecular mechanisms acting in the inner ear, extensive pedigrees with monogenic hearing loss and naturally occurring mouse mutants are used. Although a large number of genes have been localised and identified up to now, the overlap between human and murine genes is very small. Therefore, many additional gene localisations are being expected. To achieve this, ENU (ethylnitrosurea) mouse mutants will be studied. Mice with a cirkling behaviour show vestibular dysfunction, which frequently is associated with hearing loss. As a consequence, cirkling mice are an obvious choice for the study of hearing impairment.This project aims at the localisation, identification and characterisation of the genes responsible for the cirkling behaviour in 2 ENU mouse mutants using positional cloning techniques. In addition, morphological studies on the mice inner ears will be performed and the hearing loss/vestibular dysfunction will be thoroughly characterised

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Functional analysis of a gene for progressive sensorineural hearing impairment. 01/01/2002 - 31/12/2004

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.

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Research team(s)

European network on GENetic DEAFness : pathogenic mechanisms, clinical and molecular diagnosis, social impact. (GENDEAF) 01/01/2002 - 31/12/2004

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.

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Research team(s)

Study of the etiology of otosclerosis. Identification of a responsible gene and analysis of the involvement of measles virus. 01/01/2002 - 31/12/2003

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.

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Research team(s)

Identification of genes involved in presbycusis. 01/01/2002 - 31/12/2003

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.

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Functional analysis of a gene for autosomal dominant progressive sensorineural hearing impairment. 01/01/2002 - 31/12/2003

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 studies on inner ear, the subcellular localization of the protein, the identification of interacting proteins and a thorough study of a DFNA5 knock-out mouse.

Researcher(s)

Research team(s)

Identification and characterization of genes involved in hearing loss and imbalance problems. 01/10/2001 - 30/09/2004

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.

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Research team(s)

Identification and characterization of genes responsible for hereditary deafness and vestibular dysfunction 01/01/2001 - 31/12/2004

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.

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Research team(s)