A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions.
BACKGROUND
Missense mutations in the GABRG2 gene, which encodes the gamma 2 subunit of central nervous gamma-aminobutyric acid (GABA)(A) receptors, have recently been described in 2 families with idiopathic epilepsy. In one of these families, the affected individuals predominantly exhibited childhood absence epilepsy and febrile convulsions.


OBJECTIVE
To assess the role of GABRG2 in the genetic predisposition to idiopathic absence epilepsies.


METHODS
The GABRG2 gene was screened by single-strand conformation analysis for mutations. Furthermore, a population-based association study assessing a common exon 5 polymorphism (C588T) was carried out.


METHODS
The sample was composed of 135 patients with idiopathic absence epilepsy and 154 unrelated and ethnically matched controls.


RESULTS
A point mutation (IVS6 + 2T-->G) leading to a splice-donor site mutation in intron 6 was found. The mutation, which is predicted to lead to a nonfunctional protein, cosegregates with the disease status in a family with childhood absence epilepsy and febrile convulsions. The association study did not find any significant differences in the allele and genotype frequencies of the common exon 5 polymorphism (C588T) between patients with idiopathic absence epilepsy and controls (P>.35).


CONCLUSIONS
Our study identified a splice-donor-site mutation that was probably causing a nonfunctional GABRG2 subunit. This mutation occurred in heterozygosity in the affected members of a single nuclear family, exhibiting a phenotypic spectrum of childhood absence epilepsy and febrile convulsions. The GABRG2 gene seems to confer a rare rather than a frequent major susceptibility effect to common idiopathic absence epilepsy syndromes.
Institute of Human Genetics, University Hospital Bonn, Rheinische Friedrich Wilhelms-University Bonn, Germany.
Colette
C
Kananura
Karsten
K
Haug
Thomas
T
Sander
Uwe
U
Runge
Wenli
W
Gu
Kerstin
K
Hallmann
Johannes
J
Rebstock
Armin
A
Heils
Ortrud K
OK
Steinlein
D000293:Adolescent; D000483:Alleles; D004832:Epilepsy, Absence / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D011963:Receptors, GABA-A / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D003294:Seizures, Febrile / Q000235:genetics* / Q000378:metabolism
D011963:Receptors, GABA-A