Genetics and physiopathology of familial epilepsy

Co-Leaders

Research center

47 bld de l'Hôpital
75651 Paris
Alexis Brice

Institution

Inserm
CNRS
Université Pierre et Marie Curie
E3C (Paris 6)

Laboratory

UMRS 1127 UMR 7225
IHU-A-ICM

Keywords

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

Publications

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. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nature Genetics 2013, Apr 26;45(5):552-5.

Baulac S, Ishida S, Mashimo T, Boillot M, FumotoN, KuwamuraM, OhnoY, TakizawaA, AotoT, UedaM, IkedaA, LeGuernE, Takahashi R, Serikawa T (2012). A rat model for Lgi1-related epilepsies. Hum Mol Genet 21(16): 3546-57

Chabrol E, Navarro V, Provenzano G, Cohen I, Dinocourt C, Rivaud-Péchoux S, Fricker D, Baulac M, Miles R, Leguern E and Baulac S. (2010) Electro-clinical characterization of epileptic seizures in LGI1-deficient mice. Brain 133(9): 2749-62.

Depienne C, Trouillard O, Gourfinkel-An I, Saint-Martin C, Bouteiller D, Graber D, Barthez-Carpentier MA, Gautier A, Villeneuve N, Dravet C, Livet MO, Rivier-Ringenbach C, Adam C, Dupont S, Baulac S, Héron D, Nabbout R, Leguern E. (2010) Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J Med Genet Jun; 47(6):404-10.

Depienne C, Bouteiller D, Keren B, Cheuret E, Poirier K, Trouillard O, Benyahia B, Quelin C, Carpentier W, Julia S, Afenjar A, Gautier G, Rivier F, Meyer S, Berquin P, Hélias M, Py I, Rivera S, Bahi-Buisson N, Gourfinkel-An I, Cazeneuve C, Ruberg M, Brice A, Nabbout R, Leguern E. (2009) Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genetics 5(2):e1000381.

Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud'homme JF, Baulac M, Brice A, Bruzzone R and LeGuern E. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the gamma 2 subunit gene. Nature Genetics 2001; 28:46-8. 

Escayg A*, Baulac S*, Moulard B*, MacDonald BT, Meisler MH, Huberfeld G, An-Gourfinkel I, Brice A, LeGuern E, Chaigne D, Buresi C and Malafosse A. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genetics 2000; 24:343-5. (*equal contribution)



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