POSSIBLE ASSOCIATION OF A SILENT POLYMORPHISM IN THE NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR SUBUNIT ALPHA-4 WITH COMMON IDIOPATHIC GENERALIZED EPILEPSIES

The alpha 4 subunit gene of the neuronal nicotinic acetylcholine recep tor (CHRNA4) has recently been identified as the first gene underlying an idiopathic partial epilepsy syndrome in human, autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE), CHRNA4 is located in the can didate region for benign familial neonatal convulsions and low-voltage EEG on chromosome 20q, In the present study, we examined the possible role of CHRNA4 in common subtypes of idiopathic generalized epilepsy (IGE), comprising childhood and juvenile absence epilepsy and juvenile myoclonic epilepsy (JME), by systematically screening the coding regi on of the gene for sequence variants, We present here a population-bas ed association study testing the hypothesis that variants of the CHRNA 4 gene confer genetic susceptibility to common subtypes of IGE, The mi ssense mutation (Ser248Phe), associated with ADNFLE, and four silent p olymorphisms in the CHRNA4 gene were genotyped in 103 IGE patients and 92 controls by polymerase chain reaction and subsequent restriction a nalysis, Without correction for multiple testing, the frequency of the T-allele of the silent CfoI bp595 polymorphism was increased in the e ntire group of IGE patients (f(T) = 0.085) compared to that in the con trols (f(T)= 0.027). The allelic association was not restricted to any subgroup of IGE with either JME or idiopathic absence epilepsies, Thi s result suggests that variation of the CHRNA4 gene, or so-far-undetec ted sequence variants near the CHRNA4 locus, confer susceptibility to the common IGE syndromes. (C) 1997 Wiley-Liss, Inc.