The role of neuronal GABA(A) receptor subunit mutations in idiopathic generalized epilepsies.
Rare GABA(A) receptor gamma2 and alpha1 subunit mutations of pathogenic effect have been described segregating in families with "monogenic" epilepsies. We now report globally on the genetic variation contained within all 16 neuronal GABA(A) receptor subunit genes from the one patient cohort. The cohort consists of GEFS(+), FS, and IGE subgroups as either sporadic cases or index cases from small families, with one index case from one large IGE family. The rarity of mutations and coding variation in general across all of the subunits suggests a low tolerance for mutations affecting GABA mediated neuronal inhibition. Characterization of the broader channelopathy load associated with susceptibility to these common epilepsies mostly with complex genetics will need to be expanded beyond the family of GABA(A) receptor subunits to all families of neuronal ion channels and their interacting molecules by systematic mutation detection associated with functional investigation of their naturally occurring genetic variations.
Epilepsy Research Program, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia. leanne.dibbens@health.sa.gov.au
L M
LM
Dibbens
L A
LA
Harkin
M
M
Richards
B L
BL
Hodgson
A L
AL
Clarke
S
S
Petrou
I E
IE
Scheffer
S F
SF
Berkovic
J C
JC
Mulley
D000818:Animals; D001921:Brain / Q000378:metabolism; D015331:Cohort Studies; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D009865:Oocytes / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics* / Q000502:physiology; D014982:Xenopus laevis
D021122:Protein Subunits; D011963:Receptors, GABA-A