Linkage analysis between idiopathic generalized epilepsies and the GABA(A) receptor alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15.
BACKGROUND
We tested the hypothesis that genetic variants within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15q11-q13 confer genetic susceptibility to common subtypes of idiopathic generalized epilepsy (IGE).


METHODS
Ninety-four families were selected from IGE patients with either juvenile myoclonic epilepsy (JME), juvenile (JAE) or childhood absence epilepsy (CAE). Cosegregation was tested between dinucleotide polymorphisms associated with the human GABA(A) alpha5, beta3 and gamma3 subunit gene cluster and three different IGE trait models.


RESULTS
Evidence against linkage to the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster was found in the entire family set and subsets selected from either CAE or JAE. In 61 families of JME patients, a maximum lod score (Zmax=1.40 at Theta(max)=0.00) was obtained for a broad IGE spectrum ("idiopathic" generalized seizure or generalized spike and wave discharges in the electroencephalogram) assuming genetic heterogeneity (alpha=0.37; P=0.06) and an autosomal recessive mode of inheritance.


CONCLUSIONS
The possible hint of linkage in families of JME patients emphasizes the need for further studies to determine whether a recessively inherited gene variant within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster contributes to the pathogenesis of "idiopathic" generalized seizures and associated EEG abnormalities in a proportion of families.
Sander
T
T
Department of Neurology, Virchow Klinikum, Humboldt University of Berlin, Germany.
Kretz
R
R
Williamson
M P
MP
Elmslie
F V
FV
Rees
M
M
Hildmann
T
T
Bianchi
A
A
Bauer
G
G
Sailer
U
U
Scaramelli
A
A
Schmitz
B
B
Gardiner
R M
RM
Janz
D
D
Beck-Mannagetta
G
G
D002884:Chromosomes, Human, Pair 15; D004827:Epilepsy / Q000235:genetics*; D005796:Genes; D008040:Genetic Linkage; D006801:Humans; D005810:Multigene Family; D011110:Polymorphism, Genetic; D011963:Receptors, GABA-A / Q000235:genetics*
D011963:Receptors, GABA-A