Research team

Cognitive Genetics (COGNET)

Expertise

We have decades of expertise in the discovery of novel genetic intellectual disability and autism . disorders. For some of these disorders, we have performed deep-phenotyping in large patient cohorts. In addition, we have studied a subset of these disorders in depth, including the fragile X syndrome with the aim of developing therapies for the patients. In these studies, we rely heavily on mouse models. We have studied many biochemical, electrophysiological and behavioral aspects of different animal models. In the fragile X syndrome, we have discovered that the inhibitory GABAergic neurons are compromised. Subsequently, we have corrected several of the abnormalities observed in disease animal models by adding drugs that interfere with the affected pathways. In the fragile X syndrome, our findings have led to the initiation of clinical trials in which we participated.

Precision Medicine Technologies (PreMeT) 01/01/2021 - 31/12/2026

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.

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Characteristics of CGG-repeats in the human genome and in disease. 01/01/2021 - 31/12/2024

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.

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Multi-well microelectrode array (MEA): a bridge to highthroughput electrophysiology. 01/05/2020 - 30/04/2024

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.

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Identification of Converging Molecular Pathways Across Chromatinopathies with Cognitive Defects. 01/11/2019 - 31/10/2023

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.

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The pleiotropic effects of ADNP in Mental Disorders (ADNPinMED). 01/11/2019 - 31/10/2022

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.

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GENOmics in MEDicine: From whole genome sequencing towards personalized medicine (GENOMED). 03/07/2019 - 31/12/2025

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.

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CGG repeats in unexplained intellectual disability. 01/07/2019 - 30/06/2022

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.

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Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy 01/03/2019 - 28/02/2022

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.

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Dissection of the AnkyrinG interactome. 01/01/2018 - 31/12/2021

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.

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The Biomolecular Interaction Platform (BIP) at UAntwerp. 01/05/2018 - 30/04/2021

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.

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A novel Biomarker for the fragile X syndrome. 01/01/2017 - 31/12/2017

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.

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Deciphering hidden inheritance patterns using frequent itemset mining techniques on high throughput genomic data. 01/10/2016 - 15/04/2020

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.

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A kinase assay as a biomarker for the fragile X syndrome. 01/06/2016 - 31/05/2018

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.

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The translational fragile X syndrome network. 01/01/2016 - 31/12/2020

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.

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Modelling syndromic autism caused by mutations in the ADNP gene. 01/01/2016 - 31/12/2018

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.

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The role of the AnkyrinG interactome in neurodevelopmental disorders. 01/10/2015 - 30/09/2019

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.

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GENOMED - Genomics in Medicine. 01/01/2015 - 31/12/2019

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.

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Pamstation 12. 19/05/2014 - 31/12/2018

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.

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    Ganaxolone treatment of fragile X syndrome. 01/05/2014 - 30/04/2016

    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.

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    Insight into the molecular mechanisms underlying neurodevelopmental disorders through the study of the ANK3 gene. 01/01/2014 - 31/12/2014

    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.

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    A double blind crossover trial of ganaxolone in patients with fragile X syndrome. 02/10/2013 - 01/10/2015

    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.

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    Deciphering hidden inheritance patterns using advanced data mining techniques on high throughput genomic data. 01/10/2013 - 31/10/2016

    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.

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    Exome sequencing to identify novel mental retardation genes. 01/01/2012 - 31/12/2012

    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.

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    Finalizing CNV-WebStore, an integrated platform for analysis, storage and interpretation of clinically relevant structural genomic variation. 01/09/2011 - 31/08/2012

    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.

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    Genetic rescue of the fragile X syndrome in a mouse model. 11/04/2011 - 10/04/2014

    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.

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    The GABA-A receptor as a therapeutic target for fragile X syndrome. 01/01/2011 - 31/12/2014

    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.

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    Identification of new dynamic changes associated with mental retardation. 01/01/2011 - 31/12/2012

    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.

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    Identification of a new candidate gene for autism in a patient with a balanced translocation. 16/08/2010 - 15/08/2011

    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.

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    Visualization GABAa Receptor Deficiencies in Fragile X Patients Using PET Scans. 01/05/2010 - 31/05/2011

    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.

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    Mechanisms of GABAergic deficiency in the fragile X syndrome. 01/01/2010 - 31/12/2013

    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.

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    A genetic rescue for fragile X syndrome in mice. 01/10/2009 - 30/09/2013

    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.

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    Visualizing the GABA(A) receptor deficiencies in fragile X patients using PET scans. 26/08/2009 - 31/08/2011

    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.

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    Identification of new dynamic changes associated with mental retardation. 01/01/2009 - 31/12/2010

    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.

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    Development of an automated detection method to trace cytogenetic invisible chromosome deviations for patients with mental retardation. 31/01/2008 - 30/01/2009

    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.

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    Detection of novel genome disorders in mental retardation. 01/01/2008 - 31/12/2011

    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.

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    Development of an array-based MLPA method for the detection of chromosome abnormalities. 01/12/2007 - 31/12/2009

    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.

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    Treatment of fragile X syndrome via the GABA-A receptor. 01/06/2007 - 31/05/2009

    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

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    Development of an array-based MLPA method for the detection of microdeleties and duplications in mental disabled. 01/05/2007 - 30/04/2009

    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.

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    Is the GABA(A) receptor a therapeutic target for treatment of the fragile X syndrome ? 01/01/2007 - 31/12/2010

    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.

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    Is GABA-A receptor a therapeutic target for the fragile X syndrome ? 01/08/2006 - 31/07/2007

    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.

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    Is GABA-A receptor a therapeutic target for the fragile X syndrome ? 01/06/2004 - 31/05/2005

    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.

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    Identification of genetic factors involved in mild mental retardation. 01/01/2004 - 31/12/2007

    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.

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    Identification of subtelomeric chromosome rearrangements. 01/01/2003 - 31/12/2004

    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.

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    Identification of genetic factors influencing the mental handicap of patients with fragile X syndrome. 01/05/2002 - 30/04/2004

    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.

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    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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    Identification and characterization of genetic factors contributing to cognitive development. 01/01/2002 - 31/12/2005

    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).

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    Identification of subtelomeric rearrangements as a cause of metal retardation 01/10/2000 - 30/09/2001

    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.

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      Characterization of transgenic fragile X rescue mice. 01/01/2000 - 31/12/2001

      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.

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        Molecular cloning of a fragile site on chromosome 12, associated with mental retardation. 01/10/1999 - 30/09/2003

        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)

        • Promotor: Kooy Frank
        • Fellow: Winnepenninckx Birgitta

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