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ANR funded project

Blanc - SVSE 1 - Physiologie, physiopathologie, santé publique (Blanc SVSE 1) 2013

Epileptogenic Developmental Disorders: Integrated approach to improve diagnosis and understanding of pathophysiological mechanisms

About 0.5 - 1% of the population has epilepsy and more than 50% of patients develop their first seizure in childhood. Etiologies of epileptogenic disorders are very heterogeneous and the group of epileptogenic developmental disorders (EDD), are now thought, in many cases, to be related to disruption of genetic factors/programs required for the coordinated timing of proliferation, migration and layering, as well as differentiation and function of neuronal cells. Among EDD, malformations of cortical development (MCDs), focal cortical dysplasias (FCDs) and epileptic encephalopathy (EEs) are frequent causes of drug-resistant pediatric disabling developmental epilepsies and intellectual deficits. Previous studies have been traditionally focused on distinct nosological groups of EDD disorders, and little integrated studies addressing molecular diagnosis, biological, pathophysiological mechanisms and developmental processes have been undertaken.
Over the last few years, our group (with the help of the ANR) has significantly contributed in the progress of scientific and medical knowledge regarding EE and MCD (lissencephaly spectrum) and paved the way for a better understanding of polymicrogyria (PMG) conditions. More recently we showed implication of centrosome- and microtubule-dependent motor proteins such as tubulin gamma 1 (TUBG1), DYNC1H1, KIF5C and KIF2A in a large spectrum of MCD with (or without) microcephaly (Poirier et al., submitted manuscript, see also the section “2.2. State of the art - Preliminary results”). However, despite these progresses and as far as EDD are concerned, unexplained cases most of which are sporadic, remain a serious challenge because of their clinical and imaging heterogeneity and also cumulative frequency. In addition, very little is known in the field of FCD.
In continuation with our previous studies, we propose to pursue efforts aiming to delineate additional genes and genetic causes, involved in unexplained forms of MCD and EE, and expand our investigations to FCD disorders, using large-scale complementary genomic studies focused on well characterized cohorts of patients. Through this genetic approach we will also explore hypotheses of constitutive and somatic mosaic mutations underlying FCD, especially FCD type I and II, and whether some forms of MCD, FCD and EE have common genetic and molecular determinants.
In parallel to these genetic investigations, we will attempt to shed lights on pathophysiological mechanisms underlying EDD, through complementary functional studies focused on the tubulins and MT-dependent proteins (i.e., KIF5C, KIF2A, DYNC1H1 and TUBG1) recently shown to be involved in MCD spectrum. The aim of these studies will be the characterization of disrupted biological and cellular processes whose roles appear to be relevant in brain development and organization. Priority will be given to the analysis of the consequences of depletion by shRNA approach and overexpression of mutated cDNA on neuronal migration and MT-dependent processes such as MT-dependent mitotic process in neuronal progenitor cells, as well as on radial glia morphology and organization, and on MT-dependent transport in post mitotic neuronal cells.



INSERM Institut National de la Santé et de la Recherche Médicale

ANR grant: 339 926 euros
Beginning and duration: mars 2014 - 42 mois


ANR Programme: Blanc - SVSE 1 - Physiologie, physiopathologie, santé publique (Blanc SVSE 1) 2013

Project ID: ANR-13-BSV1-0009

Project coordinator:
Monsieur Jamel CHELLY (Institut National de la Santé et de la Recherche Médicale)


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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.