Genetics and physiopathology of epilepsy

Co-Leaders

Research center

47 bld de l'Hôpital
75651 Paris
Alexis Brice

Institution

Inserm
CNRS
Université Pierre et Marie Curie
ED3C - n°158

Laboratory

UMRS 1127 UMR 7225
IHU-A-ICM; ERC Consolidator Grant

Keywords

human genetics
Epilepsy molecular and cellular brain development
Transmission synaptique Epilepsie Cortex
physiopathology
Available to host a PhD student

Publications

Boillot M, Lee CY, Allene C, Leguern E, Baulac S*, Rouach N* (2016). LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development. Scientific Reports. Feb 16;6:21769. *co-last

Marsan E, Ishida S, Schramm A, Weckhuysen S, Muraca G, Lecas S, Liang N, Treins C, Pende M, Roussel D, Le Van Quyen M, Mashimo T, Kaneko T, Yamamoto T, Sakuma T, Mahon S, Miles R, Leguern E, Charpier S, Baulac S. (2016) Depdc5 knockout rat: A novel model of mTORopathy. Neurobiol Dis 89:180-189.

Weckhuysen S, Marsan E, Lambrecq V, Marchal C, Morin-Brureau M, An-Gourfinkel I, Baulac M, Fohlen M, Kallay Zetchi C, Seeck M, de la Grange P, Dermaut B, Meurs A, Thomas P, Chassoux F, Leguern E, Picard F, Baulac S. (2016) Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 57:994-1003. Article awarded the 2017 Clinical Epilepsia Prize.

Baulac S, Ishida S, Marsan E, Miquel C, Biraben A, Nguyen DK, Nordli D, Cossette P, Nguyen S, Lambrecq V, Vlaicu M, Daniau M, Bielle F, Andermann E, Andermann F, Leguern E, Chassoux F, Picard F (2015). Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol. Apr;77(4):675-83. Article highlighted as Best Advances of 2015: Picks from the Neurology Today Editorial Advisory Board

Ishida S, Picard F, Rudolf G, Noé E, Achaz G, Thomas P, Genton P, Mundwiller E, Wolff M, Marescaux C, Miles R, Baulac M, Hirsch E, Leguern E and Baulac S (2013). Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nature Genetics, Apr 26;45(5):552-5. Highlighted in Nature Review Neurology 

Fields of research

Neurogenetics / neurodevelopment

Research Theme

O

Epilepsy consists of a wide range of syndromes, all associated with abnormal synchronous neuronal firing in one or more brain regions. It is the most common neurological disorder, affecting about 1% of the population. Great progress has been made in understanding the molecular bases of inherited epilepsies, over the past two decades. Our team contributed significantly to these advances by identifying three mutated genes: SCN1A (encoding the neuronal α1 subunit of the voltage-gated sodium channel), GABRG2 (encoding the γ2 subunit of the GABAA receptor) linked to generalized epilepsy with febrile seizures (GEFS+) and DEPDC5 in familial focal epilepsies. We also identified mutations in SCN1A and PCDH19, in sporadic cases of the Dravet Syndrome (DS), a severe epileptic encephalopathy associated with febrile seizures. A second major project of the team is devoted to the non-ion channel LGI1, Leucine-rich glioma-inactivated 1, gene, linked to Autosomal Dominant Lateral Lobe Epilepsy (ADLTE). We have generated and studied Lgi1-deficient mice and a Lgi1-mutant rat. These animals reproduce most features of the human epilepsy, facilitating our studies on the patho-physiological mechanisms involved.

Our work on the epilepsies ranges from fundamental to translational research and is based on an integrated approach that combines genetics and physiopathology. Our major objectives are to unravel the etiology of selected monogenic epilepsies and to clarify mechanisms of pathogenesis with specific cellular and animal models. Today, the genetic approach is devoted to the identification of new genes responsible for i) febrile seizures associated to epilepsy, ii) epileptic encephalopathies (severe myoclonic epilepsy of infancy) and iii) familial focal epilepsies. Dominant as well as recessive forms are studied, the latter being investigated in collaboration with neurology departments in Maghreb countries. We are using family-based linkage studies to whole-exome sequencing to search for new genes. Functional consequences of mutations are investigated in transfected mammalian cells.



Team members

Elise Marsan
Christel Depienne
Virginie Lambrecq
Eric Noé
Théo Ribierre
GIuseppe Muraca
Manon Quiquand