Novel GABRG2 mutations cause familial febrile seizures.
paper
Cited
Public
- Authors
- Boillot, Morgane; Morin-Brureau, MΓ©lanie; Picard, Fabienne; Weckhuysen, Sarah; Lambrecq, Virginie; Minetti, Carlo; Striano, Pasquale; Zara, Federico; Iacomino, Michele; Ishida, Saeko; An-Gourfinkel, Isabelle; Daniau, Mailys; Hardies, Katia; Baulac, Michel; Dulac, Olivier; Leguern, Eric; Nabbout, Rima; Baulac, StΓ©phanie
- Year
- 2015
- Journal
- Neurology. Genetics
- PMID
- 27066572
- DOI
- 10.1212/NXG.0000000000000035
- PMCID
- PMC4811385
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 Ξ³2 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 Ξ³2 subunit is the probable underlying pathogenic mechanism.
Pedigrees of the families with GABRG2 mutation segregationPedigrees of family A (p.Glu402fs*3), family B (p.Arg136*), family C (p.Val462fs*33), family D (p.Pro59fs*12), family E (p.Met199Val), and family F (GABRG2 deletion) are represented. The respective GABRG2 mutations (NM_000816.3) are indicated. Individuals who carry a heterozygous GABRG2 mutation are denoted by m/+, and those negative for mutations are denoted by +/+. Arrows indicate index cases.
Schematic representation of the Ξ³2 subunit of the GABAA receptor with the position of all reported point mutationsDisease-causing point mutations in GABRG2 include 8 missense mutations,7,22,24,26,27,30,31 4 nonsense mutations,20,23,29,41 4 frameshifts,25 and 2 splice-sites.28,31 Mutations indicated by a blue star were identified in this study; those indicated by a red star were previously reported. All mutations are reported on the immature peptide. Protein structure was designed according to UniProt database information (NP_000807.2).
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