Ongoing projects

Past projects

Strengthening the Sfax University expertise for diagnosis and management of epilepctic encephalopathies (SEED). 01/10/2019 - 31/01/2023

Abstract

Epileptic encephalopathies (EE) are heterogeneous epilepsy syndromes associated with severe cognitive disturbance. EE vary in their age of onset, seizure types, electroencephalographic patterns and etiologies. New molecular technologies significantly increased the genetic diagnosis rate. In line with EU orientations and Twinning requirements, the SEED project will provide Sfax University (SU), with capacity building in excellence and innovation for earlier clinical and genetic diagnosis of EE, thanks to collaboration with Aix-Marseille University (AMU) and University of Antwerp (UA), two internationally leading organisations for the diagnosis of EE. Early clinical and genetic diagnosis allows more targeted early management, improves prognosis and thereby reduces health costs. The SEED project will: 1) strengthen the medical and technological capacity of SU in the use of innovative technologies of SU in the field of EE 2) allow access to scientific excellence at international level for members of the SU which will ultimately lead to a better integration into international networks in MENA and EU regions. The successful implementation of this strategy will rely on specific actions including: 1) enhancement of the existing and the creation of new innovative scientific and technical collaborations through short-term staff exchanges and short-term on-site training activities; 2) training of young researchers from SU to become trainers; 3) creation of an experts' network for EE management centered at SU; 4) increasing of awareness among the patients' families through targeted dissemination and communication activities and 5) development of a strategy to sustain network activity beyond the project deadline. Through the completion of these activities, and with the support of AMU and UA, SU will be able to significantly reduce networking gaps, to increase its ability to compete for international research funds and to link further with stakeholders. In addition, thanks to the SEED project, SU will become the reference center for the clinic and genetic diagnosis of EE in the MENA region.

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Project type(s)

  • Research Project

The silence of the mutant: towards a targeted therapy for KCNQ2-encephalopathy. 01/01/2019 - 31/12/2022

Abstract

KCNQ2-encephalopathy (KCNQ2-E) is a subtype of severe epilepsy, characterized by neonatal seizures and a severe developmental impairment. The disorder is caused by mutations in KCNQ2. As in other epileptic encephalopathies (EEs), all currently available treatments purely target seizures, whereas the neurodevelopmental outcome is at least as devastating for the quality of life. There is thus a strong need for new therapies that target both aspects of the disease. We will perform an in vitro proof of concept study for RNA interference as a targeted treatment strategy for KCNQ2-E, using 2D neuronal cultures derived from human induced pluripotent stem cells (hiPSC), in which we aim to tackle both disease components. Since KCNQ2-E is proven to be caused by dominant-negative or gain-of-function variants, and KCNQ2-haploinsufficiency is known to cause a self-limiting neonatal epilepsy with normal development (Benign Familial Neonatal Epilepsy (KCNQ2-B)), mutant allele specific silencing seems a promising treatment approach. Using mutant specific short hairpin RNAs, we aim to revert the electrophysiological KCNQ2-E neuronal culture phenotype to the benign KCNQ2-B phenotype. In parallel, we will generate brain organoids to more precisely model and study the neurodevelopmental process and deficits in KCNQ2-E, and provide a more advanced screening model for future treatments. When successful, this approach could be extended to many other EEs with similar mutation characteristics.

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  • Research Project

Allele-specific silencing of mutant KCNQ2 as a targeted treatment for KCNQ2 encephalopathy: an in vitro proof of concept study. 01/10/2018 - 30/09/2023

Abstract

Epilepsy is the forth most common neurological disorder, affecting around 50 million of people worldwide. The epileptic encephalopathies (EEs) are a heterogeneous subgroup of severe epilepsies with onset in the first years of life, which are characterized by treatment resistant seizures and developmental slowing or regression. The majority of EEs have a monogenic basis, and recent advances in gene discovery have greatly increased our neurobiological insights in these disorders. KCNQ2 encephalopathy, caused by mutations in the gene KCNQ2 as described in our research group, is the prototype and most frequent form of EE with neonatal onset. Seizures in these patients often respond poorly to the available anti-epileptic drugs, and more importantly, therapies targeting the neurodevelopmental problems are currently unavailable. In this project we aim to provide evidence for a targeted treatment strategy that has the potential to improve the developmental outcome of these patients. Using neuronal cultures derived of blood cells from patients with KCNQ2 encephalopathy as a disease model, we will study the treatment potential of RNA interference, a biological process that can be exploited to reduce the expression of a disease causing allele. Doing so, we aim to reverse both the epileptic and neurodevelopmental features of EEs. If successful, such an approach can be extended to many more EEs with similar characteristics.

Researcher(s)

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Project type(s)

  • Research Project

Studying the mechanisms of developmental delay in KCNQ2 encephalopathy using patient derived brain organoids. 01/10/2018 - 30/09/2022

Abstract

Epilepsy is one of the most common neurological disorders, characterized by spontaneous recurrent seizures. KCNQ2 encephalopathy (KCNQ2-E) is a severe subtype of epilepsy, characterized by seizures that appear in the first weeks of life, and a severe developmental delay for which no cure is available. The disorder is caused by a mutation in the KCNQ2 gene, encoding a potassium channel in the brain that is very important for the communication and development of neurons. In this project we will study the cause of the developmental problems of KCNQ2-E, since this is so far not understood, and seems to be at least partially independent from seizure activity. As a model we will use brain organoids, which are 3D structures derived from patient's pluripotent stem cells that represent the fetal brain in vitro. Brain organoids are a good model voor our project, because of the more complex cell interactions compared to 2D cultures. They can also generate human brain structures that are absent in animal models. The forebrain organoids will be characterizedmorphologically and electrophysiologically and compared to control organoids, with the eventual aim to understand the mechanisms underlying the developmental delay and to develop a potent read-out system for future therapeutic studies.

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  • Research Project

VIB-Sophies Award for Young KCNQ2 investigators. 22/06/2018 - 31/12/2018

Abstract

KCNQ2 encephalopathy is a severe neonatal epilepsy syndrome accompanied by intellectual disability. The disorder is caused by de novo mutations in a gene encoding for a voltage gated potassium channel subunit, KCNQ2. Seizures occur very frequent, and even if they can be controlled by anti-epileptic drugs, children are left with severe developmental problems. This prize was offered by the KCNQ2 encephalopathy patient organisation, to elucidate the pathomechanisms underlying this severe disorder, with the aim to develop better therapies.

Researcher(s)

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Project type(s)

  • Research Project

In vitro proof of concept study for RNA interference as a treatment for KCNQ2 encephalopathy. 05/04/2018 - 04/04/2019

Abstract

Epilepsy is the forth most common neurological disorder, affecting around 50 million of people worldwide. The epileptic encephalopathies (EEs) are a heterogeneous subgroup of severe epilepsies with onset in the first years of life, which are characterized by treatment resistant seizures and developmental slowing or regression. The majority of EEs have a monogenic basis, and recent advances in gene discovery have greatly increased our neurobiological insights in these disorders. KCNQ2 encephalopathy, caused by mutations in the gene KCNQ2 as described in our research group, is the prototype and most frequent form of EE with neonatal onset. Seizures in these patients often respond poorly to the available anti-epileptic drugs, and more importantly, therapies targeting the neurodevelopmental problems are currently unavailable. In this project we aim to provide evidence for a targeted treatment strategy that has the potential to improve the developmental outcome of these patients. Using neuronal cultures derived of blood cells from patients with KCNQ2 encephalopathy as a disease model, we will study the treatment potential of RNA interference, a biological process that can be exploited to reduce the expression of a disease causing allele. Doing so, we aim to reverse both the epileptic and neurodevelopmental features of EEs. If successful, such an approach can be extended to many more EEs with similar characteristics.

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

Identification of novel disease genes in rare sib pairs with epileptic encephalopathies. 01/04/2018 - 31/03/2019

Abstract

Epilepsy is the fourth most common neurological disorder, affecting around 50 million of people worldwide. While 70% of individuals with epilepsy respond well to currently available anti-epileptic drugs, one third of people continues to present seizures despite multiple drug trials. Understanding the underlying causes and mechanisms of epilepsy is an important step for the development of novel treatments. The epileptic encephalopathies (EEs) are a heterogeneous subgroup of severe epilepsies with onset in the first years of life, which are characterized by treatment resistant seizures and developmental slowing or regression. The majority of EEs have a monogenic basis, and recent advances in gene discovery have greatly increased our neurobiological insights in these disorders. Nevertheless, the genetic cause of around 60-70% of EEs still remains unknown. In this project, we will conduct whole exome sequencing on a collection of very rare affected sib pairs with EEs in which mutations in known genes have been excluded previously. We thus will uncover novel genes for EE, improve diagnostics, and increase our understanding of the mechanisms leading to the disease. This is indispensable for future novel targeted treatment development, a much needed task for these severe disorders that are highly drug resistant.

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  • Research Project

La myosite à inclusions, une maladie inflammatoire dégénératif : une approche protéomique afin d'identifier les mécanismes perturbant l'homéostasie protéinique. 01/01/2018 - 31/12/2018

Abstract

La myosite à inclusions sporadique (MIS), est la myopathie la plus fréquente après l'âge de 50 ans. MIS est une maladie intrigante de la musculature squelettique. Phénotypiquement, la maladie est caractérisé par une faiblesse progressive sélective des fléchisseurs des poignets et des doigts en du quadriceps. Une biopsie musculaire montre des infiltrats inflammatoires (la myosite) et des inclusion protéinique (des vacuoles dites 'bordées'). L'objectif du projet est de mieux comprendre les mécanismes pathophysiologiques de MIS afin de développer des 'biomarqeurs' diagnostiques et des stratégies thérapeutiques. Il y a des similarités frappantes entre MIS est les maladies neurodégénératives, notamment la présence dans les muscles atteintes d'au moins de 15 protéines caractéristiques de la maladie d'Alzheimer. Basé sur connaissance préalable, nous postulons que la cause fondamentale est une perturbation de l'homéostasie des protéines. Nous allons nous servir de l'avantage de l'accès direct au 'tissu de maladie' sous la forme des biopsies musculaire diagnostiques. Ça nous permet de réaliser une approche protéomique, dans laquelle l'ensemble complet des protéines est identifié. Actuellement, les tissus musculaires de 32 patients avec une diagnostique de MIS sont l'objet d'investigations. Nous nous préparons pour les expérimentes de validation sous forme western blot. La bourse serais utilisé pour financer ces expérimentes indispensables.

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  • Research Project

Genetics of epileptic encephalopathies - from genotype-phenotype correlation to disease modeling in zebrafish 01/10/2017 - 30/09/2019

Abstract

Dravet syndrome (DS) is a severe epilepsy disorder with a significant impact on the quality of life of both patient and parents. It is characterized by fever-sensitive epileptic seizures starting in the first year of life which are soon followed by mental decline. DS has a genetic cause and in ca. 80 % a causative genetic defect is found in the SCN1A gene. However, in remaining patients the causative genetic defect is still unknown. Currently our research group is analyzing research data of Whole Exome Sequencing on 28 SCN1Amutation- negative DS patients in a search to discover novel genes implicated in DS. We already identified some interesting candidate genes. The aim of my project is to select the most promising candidate genes and establish their causative character through functional validation studies. I will do this by studying the epilepsy phenotype in zebrafish modeling deficiency of these novel genes implicated in DS. Subsequently I will perform large follow-up studies on these novel genes, enabling me to formulate genotype-phenotype correlations. Discovery of additional genes involved in DS will have the immediate consequence that a correct, early diagnosis and genetic counselling can be offered to both physicians and parents. Moreover, functional validation in zebrafish will help us understand the pathophysiology of DS and may form a point of application for pharmacological studies which could uncover potential therapeutic strategies for this devastating disorder.

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  • Research Project

Tackling the missing heritability of inherited peripheral neuropathies: towards improved patient care, better mechanistic insights and identification of determinants driving phenotypic diversity. 01/10/2016 - 30/09/2020

Abstract

Inherited Peripheral Neuropathies (IPN) constitute a large and diverse group of disorders causing length-dependent neurodegeneration of axons in the peripheral nervous system (PNS). As many other neuromuscular disorders, IPN are chronic, debilitating and in some instances life-threatening conditions resulting in tremendous disease burden for patients and society. Affecting 1 in 2500 individuals, IPN share the challenges common to other 'rare disorders' namely substantial delays in diagnosis due to lack of reliable diagnostic tools; lack of specialized centres and standards for optimal patient care; lack of fundamental understanding of the mechanisms of disease and the absence of effective therapies. For three types of IPN (pure motor forms, pure sensory forms and congenital forms) the 'missing heritability' is as high as 70%. In this project we will start from biobanking of patients with the above-mentioned understudied types of IPN and we will systematically map out the phenotypic characteristics. In parallel, we will conduct large-scale genetic studies using next-generation sequencing techniques in these cohorts. By doing so we will tackle the existing knowledge gap in the genetic groundwork of PNS disease. This will evidently improve patient diagnosis but will at the same time significantly enlarge our understanding of the crucial mechanisms leading to axonal degeneration of the peripheral nervous system. Thirdly we aim to study the striking variability in disease severity of IPN through detailed genotype-phenotype correlation. Ultimately this will facilitate future studies designing reliable 'disease biomarkers' amenable for disease severity assessment on the one hand and the identification of novel targets for future therapeutic strategies on the other hand.

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Project type(s)

  • Research Project

VIB-Inherited muscle disorders: from single genes to disease signatures. 01/01/2016 - 31/12/2016

Abstract

Hereditary myopathies are a group of rare disorders affecting the skeletal muscles. Diagnosis is based on clinical findings, results of electromyography and MRI of muscles as well as the study of muscle biopsy. Although the spectrum of causal genes for these disorders is already broad many patients still do not have a precise diagnosis at this moment. In this project we will apply next-generation sequencing techniques in order to elucidate the genetic architecture of these disorders. We have selected 50 patients who currently do not have a genetic diagnosis for their myopathy. We will use these robust modern technologies to identify several novel genes for inherited myopathies. The goal is to improve molecular diagnostics in patients, deepen our insights in the underlying disease mechanisms and finally to designate targets for future therapeutic strategies.

Researcher(s)

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  • Research Project

Genomics of inherited neuromuscular disorders and beyond: towards the development of novel biomarkers and therapies. 01/10/2015 - 30/09/2020

Abstract

Neuromuscular disorders (NMD) form a large and diverse group of usually genetic diseases affecting spinal cord, peripheral nerve, neuromuscular junction and muscle. Most NMD are 'rare disorders' affecting less than 1 in 2000 individuals but the estimated total of 5000-7000 rare disorders affect 30 million Europeans. Most NMD are chronic, debilitating and often life-threatening resulting in tremendous disease burden for patients and society. The common challenges in NMD are: substantial delays in diagnosis due to lack of reliable diagnostic tools; lack of specialized centres and standards for optimal patient care; lack of fundamental understanding of the mechanisms of disease and the absence of effective therapies. In this project we will focus on inherited disorders of the peripheral nerve and skeletal muscle. First we will conduct large-scale genetic studies to improve patient diagnosis and to increase our understanding of the crucial mechanisms leading to the disease. Secondly we aim to study the striking variability in disease severity of NMD and confront this with the study of patient-derived tissues such as skin and muscle biopsies. This will help in the design of reliable 'disease biomarkers' that can be used to predict severity of disease and can also serve as a tool to follow the response to experimental therapies. Lastly we will use patient derived tissues to help identifying novel targets and strategies for future therapy of NMD.

Researcher(s)

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Project type(s)

  • Research Project

In vivo modeling of epileptic encephalopathies caused by mutations in aminoacyl-tRNA synthetases in zebrafish. 01/10/2015 - 30/09/2018

Abstract

Epileptic encephalopathies (EE) are serious chronic neurological disorders hallmarked by early onset and refractory seizures. They are usually caused by genetic factors, although in most cases the causative genes are unknown. Therefore there is a growing need for novel neurodevelopmental vertebrate models. Zebrafish has emerged as a promising model organism for the study of a variety of central nervous system disorders including epilepsy because of their rich behavioral repertoire that is amenable to both genetic and pharmacological manipulation. Thus, we aim in this research project is to generate and characterize novel in vivo zebrafish models for human EE caused by mutations in aminoacyl-tRNA synthesases (ARS). We will model a deficiency of these novel genes implicated in EE in zebrafish using genome editing tools and look for evidence of an epilepsy phenotype based on genetic and electrophysiological methods. Our goal is to attain new insights into the etiology of ARS-induced EE. This in vivo functional validation will help us to understand the pathophysiology of EE, and additionally will form a starting point for future pharmacological studies, which may uncover potential therapeutic strategies for improved seizure control that could be utilized for the discovery and development of new antiepileptic drugs with novel mechanisms of action.

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

Genetics of Dravet syndrome – from genotype-phenotype correlations to disease modeling in zebrafish. 01/10/2015 - 30/09/2017

Abstract

Dravet syndrome (DS) is a severe epilepsy disorder with a significant impact on the quality of life of both patient and parents. It is characterized by fever-sensitive epileptic seizures starting in the first year of life which are soon followed by mental decline. DS has a genetic cause and in ca. 80 % a causative genetic defect is found in the SCN1A gene. However, in remaining patients the causative genetic defect is still unknown. Currently our research group is analyzing research data of Whole Exome Sequencing on 28 SCN1Amutation- negative DS patients in a search to discover novel genes implicated in DS. We already identified some interesting candidate genes. The aim of my project is to select the most promising candidate genes and establish their causative character through functional validation studies. I will do this by studying the epilepsy phenotype in zebrafish modeling deficiency of these novel genes implicated in DS. Subsequently I will perform large follow-up studies on these novel genes, enabling me to formulate genotype-phenotype correlations. Discovery of additional genes involved in DS will have the immediate consequence that a correct, early diagnosis and genetic counselling can be offered to both physicians and parents. Moreover, functional validation in zebrafish will help us understand the pathophysiology of DS and may form a point of application for pharmacological studies which could uncover potential therapeutic strategies for this devastating disorder.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Pathophysiology of epileptic encephalopathies: insights from genetics in patients and in vivo modelling in zebrafish and fruit flies. 01/01/2015 - 31/12/2018

Abstract

In this project we aim to further identify novel genes implicated in epileptic encephalopathies ( pathophysiology by applying NGS strategies in combination with in vivo modelling in zebrafish. Furthermore, we envisage unravelling the pathophysiology of these newly identified genes in mutagenized fruit flies.

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

Dysfunctional endocytosis in epilepsy. 01/01/2015 - 31/12/2017

Abstract

This project aims to take advantage of epileptic encephalopathies (EE) as a genetic model to unravel and subsequently to functionally investigate uncharacterized proteins of the synaptic vesicle endocytosis pathway. So, the front-end of this project is a genetic discovery part in severe epilepsy patients to unravel mutations in proteins likely to be involved in synaptic vesicle endocytosis. The second and main part of this project is the in vivo characterisation of one of the already identified genes (DGKD) in transgenic fruit flies by using state-of-the-art complementary techniques, including electrophysiology, live imaging and electron microscopy. Not only will these findings be of importance for understanding the pathophysiology of EE, but they will also further unravel the cell biology of synaptic vesicle endocytosis; a crucial process in neuronal communication and brain homeostasis.

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  • Research Project

Dysfunctional endocytosis in epilepsy. 01/10/2014 - 31/05/2015

Abstract

In this proposal I aim to take advantage of epileptic encephalopathies (EE) as a genetic model to unravel and subsequently to functionally investigate uncharacterized proteins of the synaptic vesicle endocytosis (SVE) pathway. Mutations in genes leading to the dysregulation of SVE were recently shown to cause EE. Via whole exome sequencing we identified variants of unknown significance in six genes likely to be involved in SVE based on indirect evidence (e.g. the protein product (1) contains domains known to be functional in SVE or (2) is involved in endocytosis, but the role in SVE is unknown). I will perform a mutation analysis of these genes in 500 EE patients by gene panel analysis, allowing me to identify mutations in multiple unrelated patients providing the necessary genetic evidence to determine causality. For causative genes identified by this approach, I hypothesize that the inappropriate neuronal firing/seizures may be due to abnormalities in the regulation of synaptic transmission. Furthermore, I will investigate the functionality of one of the already identified causative genes in vivo by creating transgenic fruit flies modelling genes deficiency using state-of-the-art methodologies and analyse these mutants using complementary techniques, including electrophysiology, live imaging and electron microscopy. Not only will these findings be of importance for understanding the pathophysiology of EE, but they will also further unravel the cell biology of SVE.

Researcher(s)

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  • Research Project

Identification and functional characterisation of variant in microRNA genes involved in epileptic encephalopathies. 01/01/2014 - 31/12/2017

Abstract

During my PhD, I will investigate the role of microRNAs in epileptic encephalopathies. Epileptic encephalopathies are a subgroup of the epilepsies, where patients have an early age-of-onset and a poor outcome, meaning that they develop cognitive impairments and that they are refractory to anti-epileptic drugs. More and more evidence is emerging that microRNAs are involved in the pathomechanism of epilepsy. The hypothesis of my project is that variants in microRNAs can be causal for these severe epilepsies. To investigate this, I will perform a variant screening in a cohort of patients with epileptic encephalopathies, followed by extensive functional characterisation of the microRNA and the variant herein. This will lead to a better insight in the pathomechanism of epileptic encephalopathies and hopefully in the discovery of new ways to target these disorders.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Co-promoter: Del-Favero Jurgen
  • Fellow: Roovers Jolien

Research team(s)

Project type(s)

  • Research Project

The European Epileptic Encephalopathies consortium. 01/01/2014 - 31/12/2016

Abstract

The main goal of this consortium is to streamline and coordinate the genetic research of epileptic encephalopathies (EEs) performed on a European level even more by bringing together all patient diagnosed with EE into one European bio-bank (biosamples + phenoptypes) and by putting together all sequencing data of different consortia/inhouse sequenced patients for meta-analyses.

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

The genetic architecture of hereditary sensory and autonomous neuropathy: an exome-wide approach. 01/01/2013 - 31/12/2016

Abstract

Hereditary Sensory and Autonomic Neuropathies (HSAN) are a clinical and genetic heterogeneous group of disorders that causes a progressive and length-dependent axonal degeneration in the peripheral nervous system (PNS). The aim is to achieve new insights in the genetic factors which contribute to axonal degeneration in the PNS by the identification of novel causal HSAN genes. Therefore we perform Whole Exome Sequencing on at least 100 individuals of a big cohort consisting of isolated HSAN patients and small families.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Fellow: Mademan Inès

Research team(s)

Project type(s)

  • Research Project

Do epimutations cause Dravet syndrome? An integrated methylome and transcriptome analysis approach. 01/01/2013 - 31/12/2015

Abstract

This project aims to unravel further aspects of the pathophysiology behind epilepsy by investigating another level of genetic complexity, namely epigenetics. Through this research we aim to identify the causal link between epimutations (methylation status) and epilepsy.

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  • Research Project

Molecular genetic analysis of epileptic encephalopathies using whole exome sequencing. 01/01/2012 - 31/12/2015

Abstract

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures provoked by hypersynchronous cerebral activity. The term epilepsy actually comprises a group of disorders which is both clinically and etiologically extremely heterogeneous. Epileptic encephalopathies (EEs) are very severe forms of epilepsy in which the epileptic activity may contribute to a progressive deterioration of cerebral functions. EEs are characterized by an early onset, cognitive impairment and refractory seizures. Since patients with EE are often severely disabled mostly present as isolated cases. Besides structural or metabolic defects EEs can be caused by genetic alterations. The aim of this project is to acquire novel insights into the genetic epilepsies, more exactly the EEs. To obtain this we will perform next generation sequencing on cohorts of well-characterized patients with EE in which structural/metabolic defects and genetic alterations in the relevant epilepsy genes have already been excluded. More precisely, patients and their unaffected parents will be studied using whole exome sequencing. With this trio-approach we will detect de novo disease-causing mutations in novel genes involved in EEs. The newly identified epilepsy genes will be further analyzed in genotype-phenotype correlation studies. These results will lead to new insights in the pathomechanisms underlying epilepsy and will provide information relevant for genetic counseling, diagnosis and treatment.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Fellow: Djémié Tania

Research team(s)

Project type(s)

  • Research Project

VIB-Application of next generation sequencing to unravel the genetic architecture of Hereditary Sensory and Autonomic Neuropathies. 01/01/2012 - 31/12/2012

Abstract

Inherited peripheral neuropathies (IPN) are clinically and genetically diverse disorders occurring in 1 out of every 2500 individuals. IPN are characterized by progressive length-dependent axonal degeneration in the peripheral nervous system (PNS) resulting in gait difficulties due to pronounced distal muscle weakness and sensory loss. In the current research project we focus on a less characterized subgroup of IPN namely Hereditary Sensory and Autonomic Neuropathy (HSAN) that are known to have a broad genetic spectrum. Consequently, the vast majority of patients remain without a genetic diagnosis today. In addition, our understanding of the disease mechanisms underlying this specific axonal degeneration in the PNS remains very incomplete. In this project we will apply new whole-exome sequencing technologies to a cohort of 20 patients from 10 families with HSAN in order to make a major breakthrough in our insights of the genetic groundwork of axonal degeneration in the PNS. This study aims to identify several new causal genes for HSAN. By doing so we will improve genetic diagnosis in patients, shed new light on the pathomechanisms of PNS axonal degeneration and help delineating common pathways that will ultimately provide a point of action for future therapeutic strategies.

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  • Research Project

VIB-ESF/EUROCORES Programme "Functional genomic variation in the epilepsies". 17/11/2011 - 31/12/2011

Abstract

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

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

Unravelling the molecular architecture of epilepsies by applying high-throughput sequencing technologies and functional assays on recessive kinships from isolated populations. 01/10/2011 - 30/09/2014

Abstract

My research project plans to further dissect the genetic etiology of epilepsies via the analysis of consanguineous families, especially from Gypsy origin, as they have a unique genetic heritage. By applying complementary strategies (SNP genotyping, CNV analysis, and next-generation sequencing) major genetic factor(s) implicated in epilepsies in this population will be detected. Once identified, the search for additional pathogenic mutations in our extended collection of epilepsy patients will start (from different ethnicities and geographic backgrounds) and the functional consequences of the mutated genes will be studied, thus providing additional evidence for the causality of the observed mutations and their contribution to the pathophysiology of epilepsy. This knowledge could facilitate the development of novel/innovative treatments, improve diagnostics, genetic counseling and disease prevention."

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  • Research Project

Molecular genetic analysis of fever-related epileptic syndromes. 01/01/2011 - 31/12/2014

Abstract

Febrile seizures are the most common convulsion disorder (2-5%), affecting children between the ages of 6 months and 6 years. Retrospective studies have also shown that 10 to 15% of all epilepsy patients previously had FS. In our research we use high-density array comparative genomic hybridization, DNA enrichment techniques and next generation sequencing to identify the disease-related genes in the linked loci of three multiplex families with fever-related epileptic syndromes (including generalized epilepsy with febrile seizures plus and temporal lobe epilepsy).

Researcher(s)

  • Promoter: De Jonghe Peter
  • Fellow: Hardies Katia

Research team(s)

Project type(s)

  • Research Project

RES - Genetics of rare epilepsy syndromes. 01/01/2011 - 31/12/2013

Abstract

Aims and objectives: (A) To create a European network for the study of the genetics of rare epilepsy syndromes. (B) To identify novel genes for monogenic forms of epilepsy including familial syndromes and EEs. (C) To provide strong candidate genes for functional studies and further genetic studies. (D) To establish genotypephenotype correlations, to identify novel disease entities and to propose diagnostic guidelines.

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

VIB-Validation of prognostic and disease biomarkers for Charcot-Marie-Tooth disease 1A (CMTA1). 01/01/2011 - 31/12/2012

Abstract

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

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

Molecular genetic analysis of epilepsies: positional cloning via CNV-analysis followed by mutation analysis of candidate genes. 01/01/2011 - 31/12/2012

Abstract

Epilepsy is a clinically and genetically heterogeneous disorder affecting ~50 million patients worldwide. So far, more than 20 genes have been implicated in epilepsy pathogenesis as a result of almost exclusively linkage studies on familial epilepsies. A significant fraction of the known "epilepsy genes" are dosage sensitive and therefore haploinsufficiency of these genes is the most likely underlying pathomechanism of several epilepsy syndromes. Furthermore, increasing evidence shows that the nature of the mutation in some of these genes, either loss-of-function or gain-of-function, determines the severity of the epileptic phenotype. Still, mutations in these genes explain only a minor portion of all genetic forms and progress in gene discovery has been slow in recent years. Thus, the molecular genetics of epilepsies remains a major challenge, where innovative approaches and unexplored strategies should be sought to speed up gene identification. We plan to further dissect the genetic etiology of epilepsies by applying "copy number variation (CNV)" analysis to identify de novo submicroscopic variations encompassing dosage sensitive genes on a cohort of patients with severe complex phenotypes and epilepsy as the core feature. Once de novo CNVs are identified, the next goal is the identification of the culprit gene within these CNVs. For this goal we will perform mutation analyses of the positional candidate genes in an extended collection of epilepsy patients, hopefully identifying other pathogenic mutations, thus providing the additional evidence for the causality of the culprit gene. Finally, identifying mutations in similar or milder epileptic phenotypes will enable us to get a better understanding of the genotype-phenotype spectrum associated with these genes, leading to improved diagnostics, genetic counseling and possibly therapy.

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  • Research Project

Identification of novel genes implicated in Charcot-Marie-Tooth neuropathies using next generation full genome sequencing. 01/10/2010 - 30/09/2012

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is clinically and genetically extremely heterogeneous. During the last two decades, molecular genetic studies have led to the successful identification of over 36 CMT-genes. Currently, only a few CMT-loci remain unresolved. This project addresses the identification of CMT-causing mutations and genes in two of them: DI-CMTA and CMT2G. Because of their private nature and large linkage intervals with high gene content, these loci so far represented a challenge for researchers. The immerging next generation sequencing technologies offer an attractive opportunity to tackle such orphan CMT-subtypes. Taking advantage of these new possibilities we aim to identify the disease-causing CMT-defects in DI-CMTA and CMT2G forms using whole genome sequencing. Once identified, we will search for additional pathogenic mutations in our extended collection of well characterized nuclear families affected with DI-CMT or CMT2, thus providing additional evidence for the causality of our findings. Our selected cohort will also be used for systematic screening of known DICMT/ CMT2-genes in order to delineate the mutation spectrum of both CMT-subtypes. Extensive genotypephenotype correlation will provide valuable insights concerning the clinical determinants of these entities and will aid future diagnostics and help uncover the neuropathy pathomechanisms.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Promoter: Jordanova Albena
  • Co-promoter: De Jonghe Peter
  • Fellow: Peeters Kristien

Research team(s)

Project type(s)

  • Research Project

Identification of molecular players and drug targets for DI-CMTC neuropathy. 01/10/2010 - 30/09/2012

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder, affecting 1/2500 individuals worldwide. The main symptoms are progressive distal muscle weakness and wasting, sensory loss, reduced tendon reflexes, and foot and hand deformities. More than 500 mutations in over 40 genes have been implicated with this type of pathology providing more accurate CMT diagnosis. However, no effective therapies are available to treat CMT patients. Dominant intermediate CMT type C (DI-CMTC) is a recently defined CMT entity, characterized by axonal degeneration and demyelination of peripheral neurons. We were the first to describe DI-CMTC and demonstrated that it is caused by specific mutations in the gene encoding for tyrosyltRNA syntethase (YARS). This application is focused on the identification of molecular players and potential drug targets for this particular subtype of CMT. We will perform a screen for genetic modifiers of neurodegenerative phenotypes present in our recently generated Drosophila DI-CMTC model. The targeted genes will be selected based on their predicted abilities to interact with drug-like compounds. In this way, we will be able to gain original knowledge on DI-CMTC pathomechanisms and to translate it into a rational and reliable drug discovery program for this and possibly other inherited and acquired neuropathies.

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  • Research Project

VIB-Genetics of the neuromuscular junction: mechanisms and disease models. 01/09/2010 - 31/08/2011

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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  • Research Project

VIB-Identification of molecular players and drug targets for CMT neuropathies. 01/07/2010 - 30/06/2013

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common human inherited neuromuscular disorder, affecting 1/2500 individuals worldwide. The main symptoms are progressive distal muscle weakness and wasting, sensory loss, reduced tendon reflexes, and foot and hand deformities. Mutations in more than 30 genes have been identified in the past 15 years providing more accurate diagnosis to CMT patients. However, no effective therapies are available to treat CMT patients. Dominant intermediate CMT type C (DI-CMTC) is a recently defined CMT entity, characterized by slowly progressive neuropathy, intermediate nerve conduction velocities along peripheral nerves and histological evidence of both axonal and Schwann cell involvement. We were the first to describe this genetic entity and demonstrated that it is caused by different mutations in the gene coding for tyrosyl-tRNA synthetase. This study will be focused on the identification of molecular players and potential drug targets for this particular subtype of CMT. We will perform a screen for genetic modifiers of neurodegenerative phenotypes present in a Drosophila model for DI-CMTC. In this way we will be able to gain original information on DI-CMTC pathomechanisms. The knowledge gained will be relevant also to other inherited and acquired neuropathies.

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  • Research Project

VIB-Identification of a novel gene implicated in Charcot-Marie-Tooth neuropathy using whole genome massive parallel sequencing. 01/05/2010 - 30/04/2011

Abstract

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

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  • Research Project

VIB-Deciphering the molecular mechanisms of neuronal dysfunction induced by DI-CMTC associated mutations in YARS using a Drosophila DI-CMTC model. 01/01/2010 - 31/12/2010

Abstract

Our current hypothesis is that DI-CMTC associated mutations in YARS may result in the activation of protein degradation pathways, either directly (e.g. due to mischarging of tRNATyr and misincorporation of non-cognate amino acids in cellular proteins) or indirectly (through interfering with downstream protein quality control pathways). In both cases, this is expected to result in overload of the UPS and activation of cellular stress responses, including induction of autophagy, ER stress and ultimately apoptosis. Here, we propose to study the potential derailment of these cellular pathways in more detail.

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  • Research Project

Molecular genetic analysis of idiopathic epilepsies: identification of novel genes by means of copy number variation (CNV) analysis. 01/01/2010 - 31/12/2010

Abstract

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  • Research Project

Large scale genetic approach for the molecular characterization of autosomal-recessive Charcot-Marie-Tooth disease. 01/10/2009 - 30/09/2011

Abstract

Most of the identified genes and loci in ARCMT have resulted from studies of large inbred families originating from particular geographic areas or specific ethnic groups (e.g. Gypsies). Although there are no reported attempts in the literature to target small families with this disease, some studies have shown that, as a proof of principle, such strategy can be successful (7, 8). Using our collection of families and by following the approach for mapping of recessive disorders together with genotyping technologies, we aim to create a powerful tool for ARCMT locus and gene identification. Furthermore, novel technologies now also allow targeting of small families.

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  • Research Project

Clinical, electrophysiological and molecular genetic characterization of HMSN type II and intermediate type of CMT. 01/10/2009 - 30/09/2011

Abstract

Clinical, neuropathological and molecular genetic characterisation of axonal and intermediate hereditary neuropathies including Hereditary Motor and Sensory Neuropathy type II (HMSN II), Hereditary Motor Neuropathy (HMN) and Hereditary Sensory and Autonomic Neuropathy (HSAN) in order to make detailed genotype-phenotype correlations. These will be instrumental in the design of diagnostic guidelines and will help orient further genetic and cell-biological studies into the disease mechanisms underlying hereditary disorders of the peripheral nervous system.

Researcher(s)

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  • Research Project

Large scale genetic approach for molecular characterization of autosomal-recessive Charcot-Marie-Tooth neuropathy. 01/01/2009 - 31/12/2012

Abstract

We aim to perform a large-scale study on the molecular basis or ARCMT, taking advantage of our unique collection of nuclear inbred families from different geographic regions and ethnic groups of the world. We will apply an approach of simultaneous genetic search for several trait-causing loci with large scale genotyping, that will allow identification of novel loci, genes and disease-causing mutations, respecting at the same time the genetic heterogeneity of ARCMT.

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Project website

Project type(s)

  • Research Project

VIB-Large scale genetic approach for molecular characterization of autosomal-recessive Charcot-Marie-Tooth disease. 01/01/2009 - 31/12/2009

Abstract

Autosomal-recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare disorders of the peripheral nervous system showing extreme clinical and genetic heterogeneity. So far eleven genes and three loci have been implicated in the pathology of only a small number of ARCMT families. Most of the genes have been identified using homozygosity mapping of large inbred families, however there are no reported attempts in the literature to target small families with this disease. Finding novel loci and genes in single patients, together with identifying the disease-causing mutations in already reported genes is a major challenge for the current research and diagnostic in this field. We propose to conduct a large-scale study on the molecular basis of ARCMT, taking advantage of our unique collection of nuclear inbred families from different geographic regions and ethnic groups of the world. We will perform large scale SNP genotyping to search simultaneously for several trait-causing loci using homozygosity mapping. Our disease model ideally suits this genetic approach, because the rarer the disease the more pronounced the homozygozity effect. Patients linked to already known loci and genes will be further analysed to identify the disease-causing mutations. Patients linked to unknown loci will be further genotyped to delineate the minimal genetic region, common to all of them. Subsequent search of positional and functional candidate genes will allow identification of novel ARCMT genes. Considering the high density of the SNP array and the degree of consanguinity in the families, we estimate that our study has the potential to identify several novel ARCMT loci and genes. The identification of genes causing ARCMT will contribute to the understanding of the pathophysiology of these disorders by revealing new disease mechanisms or strengthen the importance of the known ones. The mutations that will be found will allow genotype-phenotype correlations and will have an important impact on the diagnostic of peripheral neuropathies, genetic counseling and disease prevention.

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  • Research Project

Large scale genetic approach for molecular characterization of autosomal-recessive Charcot-Marie-Tooth neuropathy. 01/12/2008 - 30/11/2009

Abstract

This study is a starting point for the creation of a unique research profile into molecular genetics of autosomal-recessive forms of Charcot-Marie-Tooth disease (ARCMT) - severe and disabling genetic disorders of the peripheral nervous system, where limited research was done so far worldwide. The identification of genes and mutations causing ARCMT will contribute to the understanding of the pathophysiology of these disorders by revealing new disease mechanisms or strengthen the importance of the known ones. This will allow genotype-phenotype correlations and will have an important impact on the diagnostic of peripheral neuropathies, genetic counseling and disease prevention. The proposed research line will add and complement to the research and diagnostic capacity and international recognition of the VIB Department of Molecular Genetics by i) implementing a specific research project that has been put on hold because of the previous lack of capacity; ii) accumulation of a critical mass of expertise; iii) initiation of further collaborations, and iv) increased output and higher quality of publications in international peer-reviewed journals. UA 2007 ¿ ZAP-Startkredieten

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  • Research Project

Unraveling the genetic basis of epilepsies - a population based approach. 01/10/2008 - 30/06/2013

Abstract

This project proposal aims to study the genetics of epilepsies in the population of European Romas (Gypsies). For this purpose the Neurogenetics group, Department of Molecular Genetics and the group of Prof. Luba Kalaydjieva, Center for Medical Research, Western Australian Institute for Medical Research will joint their patient collections, data and expertise to gain original knowledge of interst for the whole scientific community and for the society. Identification of loci and genes influencing susceptibility to epilepsy could facilitate early identification of individuals at risk and their adequate treatment.

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  • Research Project

Molecular genetic studies of inherited epilepsies. 01/01/2008 - 31/12/2011

Abstract

General aims: (1) Recruiting en characterization of additional patients and families; (2) Locus and gene-identification studies; (3) Mutations analyses and studies on SCN1A in the context of SMEI; (4) Mutation analysis of known genes.

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

Prize Research Council 2007. 19/12/2007 - 31/12/2007

Abstract

Researcher(s)

  • Promoter: Claes Godelieve

Research team(s)

Project type(s)

  • Research Project

Clinical, electrophysiological and molecular genetic characterization of HMSN type II and intermediate type of CMT. 01/10/2007 - 30/09/2009

Abstract

Clinical, neuropathological and molecular genetic characterisation of axonal and intermediate hereditary neuropathies including Hereditary Motor and Sensory Neuropathy type II (HMSN II), Hereditary Motor Neuropathy (HMN) and Hereditary Sensory and Autonomic Neuropathy (HSAN) in order to make detailed genotype-phenotype correlations. These will be instrumental in the design of diagnostic guidelines and will help orient further genetic and cell-biological studies into the disease mechanisms underlying hereditary disorders of the peripheral nervous system.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Identification of novel genes involved in idiopathic epilepsies using comparative genome hybridization (CGH) 01/10/2006 - 30/09/2008

Abstract

The aim of this project is the identification of novel genes predisposing to epilepsy. We hypothesize that some patients with a syndromal form of epilepsy harbour a chromosomal rearrangement like a deletion or duplication. Therefore, the epilepsy is part of a contiguous gene syndrome and the gene responsible for the epilepsy phenotype must reside in the deleted or duplicated region. We expect that point mutations in these genes can cause similar epilepsy syndromes, like has been shown for 'severe myoclonic epilepsy of infancy' (SMEI) and 'generalized epilepsy with febrile seizures plus' (GEFS+). Therefore, these newly identified genes will be analyzed in patients with an idiopathic epilepsy.

Researcher(s)

  • Promoter: Claes Godelieve

Research team(s)

Project type(s)

  • Research Project

Clinical, electrophysiological and molecular genetic characterization of HMSN type II and intermediate type of CMT. 01/10/2006 - 30/09/2007

Abstract

Clinical, neuropathological and molecular genetic characterisation of axonal and intermediate hereditary neuropathies including Hereditary Motor and Sensory Neuropathy type II (HMSN II), Hereditary Motor Neuropathy (HMN) and Hereditary Sensory and Autonomic Neuropathy (HSAN) in order to make detailed genotype-phenotype correlations. These will be instrumental in the design of diagnostic guidelines and will help orient further genetic and cell-biological studies into the disease mechanisms underlying hereditary disorders of the peripheral nervous system.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Co-promoter: Claeys Kristl
  • Fellow: Baets Jonathan

Research team(s)

Project type(s)

  • Research Project

Clinical characterization and genotype-phenotype correlations in idiopathic epilepsies. 01/03/2006 - 28/02/2007

Abstract

The aim of the current project is to collect new families with diverse forms of idiopathic epilepsy, and to define new clinical-genetic entities based upon genotype-phenotype correlations. Families that show no mutations in the known genes and have been excluded for linkage to the known loci will be further investigated with genome-wide scans. The molecular genetic research aiming at the identification of new epilepsy loci and genes has important implications for diagnostics and therapies.

Researcher(s)

  • Promoter: Claeys Kristl

Research team(s)

Project type(s)

  • Research Project

Inherited Peripheral Neuropathies. 01/01/2006 - 31/12/2010

Abstract

The inherited peripheral neuropathies are a heterogeneous group of disorders. Currently, based on genetic locus information, more than 50 subtypes are known of which the underlying genetic defect is identified in 30 variants. Recently the first successful therapeutic approaches have been reported in two animal models of the most common subtype. To further elucidate the underlying genetic defects, to study the celbiological consequences and to translate this knowledge in therapeutic approaches in humans, the close collaboration between clinicians, geneticists and celbiologists is required. Within the research domain of the inherited peripheral neuropathies there already exist a long tradition of collaborations within the European CMT consortium, coordinated by our laboratory, and the more recently formed North American CMT consortium; a first joint meeting between the two consortia was organized in Antwerp, Belgium, in 2004. Within the FWO network we have gather all renowned research groups working on the inherited peripheral neuropathies in order to strengthen ongoing collaborations and initiate novel initiatives.

Researcher(s)

  • Promoter: De Jonghe Peter

Research team(s)

Project type(s)

  • Research Project

Genetic studies of inherited complex epilepsies. 01/10/2005 - 30/09/2008

Abstract

The epilepsies are a group of common neurological disorders, affecting about 1% of the population at some time in their lives. Family and twin studies provided evidence for a genetic component in the etiology of epilepsy, but often the mode of inheritance is complex. Genetic studies in large families in which epilepsy segregates in an autosomal dominant mode with reduced penetrance led to the identification of mutations in 14 genes. So far, only a small number of mutations have been described in all these genes, with the exception of mutations in SCN1A associated with severe myoclonic epilepsy in infancy (SMEI). Since our first report [1], more than 100 SCN1A mutations have been identified [2,3]. Still, this indicates that a large number of genes are still to be found. In this project we aim to extend our mutation analysis of SCN1A to more complex mutations like gene deletions and mutations in regulatory sequences. Aiso, we will perform an association study to assess the contribution of certain genetic variations to the epilepsy phenotype. In addition, we aim to identify the genetic defect in a large family affected with an epilepsy syndrome linked to a novellocus on chromosome 12. Since the genetic defect most probably occurs in a gene that does not code for an ion channel, this study can lead to novel insights into the pathomechanism of epilepsy.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Fellow: Claes Godelieve

Research team(s)

Project type(s)

  • Research Project

Hereditary spastic paraplegia: genetic, clinical and pathological research. 01/10/2005 - 31/12/2007

Abstract

The project aims at identifying pathogenic mutations associated with HSP. The identification of pathogenic mutations creates opportunities for better DNA diagnosis and provides possibilities to perform genotype/phenotype correlations. In large HSP families without a mutation in the known genes a genome wide search will be performed to identify novel loci and novel genes for HSP.

Researcher(s)

  • Promoter: Nelis Eva

Research team(s)

Project type(s)

  • Research Project

Molecular genetics of idiopathic epilepsies. 01/01/2005 - 31/12/2006

Abstract

Epilepsy is one of the most common neurologic disorders, with a cumulative life-time incidence of about 3%. The epilepsies can be classified according to their etiology. For the idiopathic epilepsies there is no underlying cause other than a possible hereditary predisposition. Molecular genetic research has already identified thirteen genes in which mutations cause epilepsy. The fact that mutations in these genes are only found in a limited part of the families indicates that the idiopathic epilepsies are genetic heterogeneous. Therefore, further research towards new genes involved in these epilepsies is essential. The main purpose of this project is the identification of new loci and genes in which mutations cause an epileptic phenotype. Initially large multiplex families are studied. In these families the responsible genetic locus is identified by linkage analysis and the candidate genes in the region are screened for disease-related mutations. For nuclear families or isolated patients we use a candidate gene approach. The selection of the candidate genes is based on their homology with genes identified in epileptic phenotypes of man and mouse. Also known epilepsy genes are analyzed in families with a similar phenotype, which gives an indication of the frequency of mutations in that gene. This allows us to make genotype-phenotype correlations. By extending the mutation analysis to other epileptic phenotypes we investigate whether mutations in the gene cause other types of epilepsy or if they act like susceptibility factors. We will also investigate the functional effects of the identified mutations in in vitro and in vivo systems. Electrophysiological experiments are used to analyze mutations in subunits of ion channels. Mouse models will help to reveal the effect of the mutation on neuronal circuits or an entire organism.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Co-promoter: Van Broeckhoven Christine
  • Fellow: Deprez Liesbet

Research team(s)

Project type(s)

  • Research Project

Identification of novel genes and disease mechanisms underlying idiopathic epilepsies. 01/01/2004 - 31/12/2007

Abstract

In this project we will continue the initiated genetic studies in patients/families with different epilepsy syndromes. This project is expected to contribute to the understanding of the genetic mechanisms operating in one of the most prevalent and most complex group of neurological disorders (Hauser et al. 1993). Epilepsies represent a highly clinically heterogeneous group with both genetically determined and acquired epilepsy syndromes. Most epilepsy syndromes are complex disorders resulting from the interaction of (multiple) genes and environmental factors (Berkovic et al. 1998). A genetic contribution has been suggested for about 40% of epilepsy patients. Recent genetic studies have indicated that several epilepsy syndromes result from mutations in ion channels: ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy) is associated with mutations in CHRNA4 and CHRNB2, while mutations in KCNQ2 and KCNQ3 lead to BFNC (benign familial neonatal convulsions). In GEFS+ (generalized epilepsy with febrile seizures plus) mutations in SCN1B, SCN1A, SCN2A and GABRG2 have been reported. More recently, we described de novo mutations in SCN1A in patients with SMEI (severe myoclonic epilepsy of infancy or Dravet syndrome). In vitro assays based on the expression of mutated ion channels allow testing of anti-epileptic activity of newly synthesized compounds. Development of new anti-epileptic drugs is needed since though existing drugs are efficient, a substantial number of patients do not become seizure-free. Also, mutations in LGI1 were shown to cause partial epilepsy with auditory features and mutations in GABRA1 are associated with JME (juvenile myoclonic epilepsy). Biochemical and morphological changes that make previously normal brain epileptic (epileptogenesis) remain largely unknown. Insight in this mechanism might eventually lead to the development of protective therapies that prevent the development of acquired forms of epilepsy e.g. after a cranial trauma. The generation of animal models based on epilepsy genes will therefore be instrumental in studying epileptogenesis. Molecular genetic studies of epilepsy syndromes have successfully identified chromosomal loci and genes using a linkage mapping in multiplex families and analysis of positional candidate genes within the respective chromosomal regions. To date, 20 loci are known for different epilepsy syndromes (Kaneko et al. 2002). However, only 10 epilepsy genes have been identified to date. Also it has been recognized that the known loci/genes explain only a limited fraction of all genetically determined epilepsy syndromes, underlining once more the huge clinical and genetic heterogeneity of this group of neurological disorders. This is exemplified by our recent finding of 4 novel loci, each one being a private locus in 1 family.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Co-promoter: Van Broeckhoven Christine

Research team(s)

Project type(s)

  • Research Project

VIB-Molecular genetics of distal hereditary motor neurpathies (distal HMN). 01/01/2004 - 31/12/2004

Abstract

The inherited peripheral neuropathies have a prevalence of 1/2500 and occur worldwide. Patients sometimes become severely handicapped at a young age. The most common clinical presentation is Charcot-Marie-Tooth neuropathy (CMT), a disorder first described in 1886 (Charcot and Marie, 1886,Tooth, 1886). CMT is characterised by progressive weakness and atrophy of foot and hand muscles. Clinical, neurophysiological, neuropathological and genetic studies have shown that this group of disorders is highly heterogeneous. According to the classification of PJ Dyck, inherited peripheral neuropathies can be categorised as hereditary motor and sensory (HMSN), hereditary motor (HMN) and hereditary sensory neuropathies (HSN). HMSN, HMN and HSN are further subdivided in several subtypes (Dyck et al., 1993). Currently no efficient therapy is available for any of these disorders. Using positional cloning methods, the chromosomal localisation (locus) of more than 30 inherited peripheral neuropathies in humans has been mapped. However, these genetic analyses also show that many entities do not show linkage to the known loci. The number of genes identified so far is 24 (see IPNMDB: molgen-www.uia.ac.be/CMTMutations) (Kuhlenbäumer et al., 2002). The functional analysis of the gene products and the construction of animal models have led to novel insights in the pathomechanisms (Suter and Scherer, 2003). This knowledge, however, remains fragmentary and the identification of new genes and functional pathways remains a high priority. In this project, we will focus on the molecular genetics of distal hereditary motor neuropathies (distal HMN) or the spinal form of CMT. The genetic characterisation of distal HMN is a first step in understanding the pathogenic mechanisms that cause these motor diseases.

Researcher(s)

  • Promoter: Nelis Eva

Research team(s)

Project type(s)

  • Research Project

Molecular genetic analysis of epilepsy syndromes. 01/10/2003 - 30/09/2005

Abstract

Epilepsy is a very frequent neurological disorder with a prevalence of 0.5% in western populations. Epilepsy is a very heterogeneous group of disorders. Genetics factors play an important role in some of the epilepsy variants. So far more than 20 genetic loci have been mapped and several genes have been identified in which mutations cause epilepsy. The aims of this project are to map novel loci for epilepsy. Subsequently the genes involved are identified. We are also performing mutation analyses of the known genes in patients with distinct epilepsy syndromes in order to make genotype-phenotype.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Co-promoter: Van Broeckhoven Christine
  • Fellow: Audenaert Dominique

Research team(s)

Project type(s)

  • Research Project

Molecular genetics of idiopathic epilepsies. 01/01/2003 - 31/12/2004

Abstract

Epilepsy is one of the most common neurologic disorders, with a cumulative life-time incidence of about 3%. The epilepsies can be classified according to their etiology. For the idiopathic epilepsies there is no underlying cause other than a possible hereditary predisposition. Molecular genetic research has already identified thirteen genes in which mutations cause epilepsy. The fact that mutations in these genes are only found in a limited part of the families indicates that the idiopathic epilepsies are genetic heterogeneous. Therefore, further research towards new genes involved in these epilepsies is essential. The main purpose of this project is the identification of new loci and genes in which mutations cause an epileptic phenotype. Initially large multiplex families are studied. In these families the responsible genetic locus is identified by linkage analysis and the candidate genes in the region are screened for disease-related mutations. For nuclear families or isolated patients we use a candidate gene approach. The selection of the candidate genes is based on their homology with genes identified in epileptic phenotypes of man and mouse. Also known epilepsy genes are analyzed in families with a similar phenotype, which gives an indication of the frequency of mutations in that gene. This allows us to make genotype-phenotype correlations. By extending the mutation analysis to other epileptic phenotypes we investigate whether mutations in the gene cause other types of epilepsy or if they act like susceptibility factors. We will also investigate the functional effects of the identified mutations in in vitro and in vivo systems. Electrophysiological experiments are used to analyze mutations in subunits of ion channels. Mouse models will help to reveal the effect of the mutation on neuronal circuits or an entire organism.

Researcher(s)

  • Promoter: De Jonghe Peter
  • Co-promoter: Van Broeckhoven Christine
  • Fellow: Deprez Liesbet

Research team(s)

Project type(s)

  • Research Project

Identification and characterisation of genes for inherited peripheral neuropathies. 01/01/2003 - 31/12/2004

Abstract

The inherited peripheral neuropathies are clinical and genetical heterogeneous. This project aims at identifying new genes and pathogenic mutations for inherited peripheral neuropathies. This will result in a better understanding of the neurobiology of the peripheral nervous system, creates opportunities for better DNA diagnosis and provides possibilities to perform genotype/phenotype correlations.

Researcher(s)

  • Promoter: Nelis Eva

Research team(s)

Project type(s)

  • Research Project

Clinical and molecular genetic research of inherited peripheral neuropathies. 01/01/2002 - 31/12/2005

Abstract

The inherited neuropathies of the peripheral nervous system have a prevalence of 1/2500. They have been observed in populations with different ethnic background. Some patients remain asymptomatic while others become severely disabled by weakness, muscle atrophy and skeletal deformities. The inherited peripheral neuropathies are genetically very heterogeneous and probably comprise between 50-100 distinct disease entities. The identification of the underlying mutations opens avenues for better diagnosis, correct genetic counseling, prenatal and pre-implantation diagnosis. This research project aims at identifying novel genes en gene defects. The identification of the genes and functional studies of the mutated gene products will result in a better understanding of the neurobiology of the peripheral nervous system. The identification of therapeutic targets potentially has implications for the acquired neuropathies that complicate e.g. diabetes mellitus and chemotherapy.

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  • Research Project