Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Genetics of cortical gyral dysgenesis and pathophysiology of tubulin-related malformations of cortical development

Project Coordinator

Institut Cochin Department of Genetics and Development INSERM


David Keays Laboratory for the Molecular Basis of Migration, Research Institute of Molecular Pathology Vienna, Austria
Renzo Guerrini Research, IRCCS Stella Maris Foundation Calambrone Pisa, Italy

Publications of the TUB-GENCODEV project

Major results of the project

Between 0.5 - 1% of the population has epilepsy and more than 50% of patients develop their first seizure in childhood. The origin of epileptogenic disorders are heterogeneous, however some are related to the disruption of genetic factors/programs required for the coordinated timing of proliferation, migration and differentiation of neurons in development. These disorders include the heterogeneous group of conditions called malformations of cortical development (MCD) such as periventricular nodular heterotopia (PVNH), lissencephaly/pachygyria (LIS spectrum), and polymicrogyria (PMG).
Our project is structured around two major scientific objectives. 
–    Objective 1: Delineation of genetic and molecular causes involved in unexplained forms of malformations of cortical developmental (MCD), in order to provide reliable tools and approaches for comprehensive diagnosis, classification and insights for a better understanding of cellular developmental bases underlying these disorders. The overall methodology and strategy to address this genetic issue are mainly be based on whole exome sequencing of trios (sporadic patients and their parents) to identify de novo mutations and thorough analysis using a prioritization scheme that takes into account results of and state of the art regarding genetics of neurodevelopmental disorders and potential pathophysiological mechanisms underlying MCD. This overall strategy will be combined with targeted screening of the candidate genes (exhibiting de novo mutations identified by WES) in additional cohorts of patients, in order to validate and reinforce genetic findings.
–    Objective 2. Further exploration of our recent findings demonstrating implication of centrosome- and MT-dependent motor proteins in MCD and investigation of MT-dependent mitotic and transport processes in the pathogenesis of developmental disorders. These investigations will rely on complementary methodologies and approaches. The first corresponds to the in utero electroporation (IUEP) approach to assess consequences of depletion by shRNA and overexpression of mutant cDNA on proliferation of neuronal progenitor, morphology and organization of radial glia cells, and neuronal post-mitotic processes (i.e., polarization, migration and early stages of differentiation). We will also focus on MT-dependent transport and trafficking of vesicles and membranes in neuronal cells (and patients fibroblasts) in order to explore whether post mitotic abnormalities concerning processes such as polarization, migration, neurite outgrowth and differentiation that require dynamic morphological changes and addition of membranes, could result from defects of MT-dependent transport, dynamics and/or organization.
In parallel to these investigation, we proposed the development of unique collection of mouse model mutants (corresponding to mutation identified in patients with MCD), including conditional knock in models in order to better define in vivo consequences of MCD-related genes dysfunction on neurodevelopmental processes, and understand molecular mechanistic underlying MCD.

The primary objectives of the project are to identify new genes that cause cortical malformations and characterize the role of the tubulin gene family in cortical development. With the identification of more than 8 novel genes (TUBB5, TUBG1, DYNC1H1, KIF2A, KIF5C, MAST1, EML1, CDC27, TBC1D23, C6ORF70) encoding either for tubulin subunits or MT-related proteins and refinement of clinical phenotypes resulting from mutations in these genes, TUB-GENCODEV consortium played a leading role in the medical and neurodevelopmental fields related to these disorders (Breuss et al., 2013; Poirier et al., 2013; Kielar et al., 2014; Bahi-Buisson et al., 2014; Conti et al., 2013; Mirzaa et al., 2015; Zillhardt et al., 2015).
The consortium has indeed significantly advanced genetic knowledge of this medical field and accelerated transfer and implementation of genetic tests in hospital and medical environments and therefore improved the diagnosis of this heterogeneous group of disorders. The consortium has also developed a unique collection of clinical imaging and biological resources integrating more than 1000 patients with MCD.
To achieve the second objective, the consortium has developed and extensively used the in utero electroporation approach and advanced analysis and definition of the consequences of TUBB3, KIF2A and TUBG1 mutations on neurogenesis and post-mitotic processes and showed that expression of TUBB3, KIF2A and TUBG1 mutants is associated with an array of deregulations that include disruption of mitotic progenitor cycle and dynamics of neuronal migration (pyramidal and interneurons) (Saillour et al., 2014; Broix et al., in preparation).
Finally, the consortium has generated 8 constitutive and conditional knock-in mouse models and undertook an ambitious program aiming to characterize and define mutations related neurodevelopmental, cellular, biological and molecular defects in order to better understand pathophysiological mechanisms underlying MCD and associated clinical phenotypes such as ID and epilepsy. Most recently, the Keays lab has published an in depth cellular and molecular characterisation of two TUBB5 mutant lines (Tubb5 KO, and Tubb5 E401K). These studies have shown that Tubb5 mutations cause microcephaly by perturbing the cell cycle and inducing p53 associated apoptosis (Breuss et al, 2016).
The efficient and constructive collaborations between partners of our consortium have also enhanced successful participations of the partners in an FP7 European proposal (DESIRE project) and an International collaborative Research project (ANR-FWF KI-models-MCD). 

E-Rare 2012 - Created by Toussaint Biger