Novel GABRG2 mutations cause familial febrile seizures

Morgane Boillot (1, 2) , Mélanie Morin-Brureau (1) , Fabienne Picard (3) , Sarah Weckhuysen (2, 1) , Virginie Lambrecq (1, 2) , Carlo Minetti (4) , Pasquale Striano (4) , Federico Zara (4) , Michele Iacomino (4) , Saeko Ishida (1) , Isabelle An-Gourfinkel (1, 2) , Mailys Daniau (1) , Katia Hardies (5, 6) , Michel Baulac (1) , Olivier Dulac (2, 7) , Eric Leguern (1, 2) , Rima Nabbout (2, 7) , Stéphanie Baulac (1)

1 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
2 CHU Pitié-Salpêtrière [AP-HP]
3 HUG - Hôpitaux Universitaires de Genève
4 UniGe - Università degli studi di Genova = University of Genoa
5 VIB11 - Department of Molecular and Developmental Genetics
6 Institute Born-Bunge
7 Hôpital Necker - Enfants Malades [AP-HP]

Objective: To identify the genetic cause in a large family with febrile seizures (FS) and temporal lobe epilepsy (TLE) and subsequently search for additional mutations in a cohort of 107 families with FS, with or without epilepsy. Methods: The cohort consisted of 1 large family with FS and TLE, 64 smaller French families recruited through a national French campaign, and 43 Italian families. Molecular analyses consisted of whole-exome sequencing and mutational screening. Results: Exome sequencing revealed a p.Glu402fs*3 mutation in the γ2 subunit of the GABAA receptor gene (GABRG2) in the large family with FS and TLE. Three additional nonsense and frameshift GABRG2 mutations (p.Arg136*, p.Val462fs*33, and p.Pro59fs*12), 1 missense mutation (p.Met199Val), and 1 exonic deletion were subsequently identified in 5 families of the follow-up cohort. Conclusions: We report GABRG2 mutations in 5.6% (6/108) of families with FS, with or without associated epilepsy. This study provides evidence that GABRG2 mutations are linked to the FS phenotype, rather than epilepsy, and that loss-of-function of GABAA receptor γ2 subunit is the probable underlying pathogenic mechanism.

Domaines: Neurosciences [q-bio.NC]

Morgane Boillot, Mélanie Morin-Brureau, Fabienne Picard, Sarah Weckhuysen, Virginie Lambrecq, et al.. Novel GABRG2 mutations cause familial febrile seizures. Neurology Genetics, 2015, 1 (4), pp.e35. ⟨10.1212/NXG.0000000000000035⟩. ⟨hal-01304648⟩