THE GENE ENCODING THE ALPHA(1A)-VOLTAGE-DEPENDENT CALCIUM-CHANNEL (CACN1A4) IS NOT A CANDIDATE FOR CAUSING COMMON SUBTYPES OF IDIOPATHIC GENERALIZED EPILEPSY

Mutations in the gene encoding the alpha(1A)-calcium channel subunit p lay a causative role in the epileptogenesis of absence seizures in tot tering mutant mice. The present family-based association and non-param etric linkage study tested the hypothesis that allelic variants of the homologous human gene (CACN1A4) confer susceptibility to common subty pes of idiopathic generalized epilepsy (IGE). An expressed polymorphic CAG trinucleotide repeat in the 3' end of the CACN1A4 gene was assess ed in 70 families ascertained through members with either childhood (C AE) and juvenile absence epilepsy (JAE), or juvenile myoclonic epileps y (JME). Our association analysis using the haplotype-based haplotype relative risk statistic provided no evidence for an allelic associatio n of the CAG repeat polymorphism with either IGE, or CAE and JAE, or J ME. We found no relation between the CAG repeat length and susceptibil ity neither to IGE, nor to CAE and JAE, nor to JME. Non-parametric lin kage analysis revealed no evidence for linkage of IGE traits with the CACN1A4 locus in 42 families of patients with either CAE or JAE. A wea k trend towards an excess of allele sharing (identity by descent) amon g family members affected by an IGE was obtained in 26 families of JME patients (Z(NPL) = 1.25 at theta = 0.000, p = 0.057). Taken together, we found no statistically significant evidence that genetic variants of the CACN1A4 gene play a causative role in the pathogenesis of commo n subtypes of IGE in humans. (C) 1998 Elsevier Science B.V.