Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit α4 with common idiopathic generalized epilepsies

Abstract

The alpha4 subunit gene of the neuronal nicotinic acetylcholine receptor (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 candidate 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 region of the gene for sequence variants. We present here a population-based association study testing the hypothesis that variants of the CHRNA4 gene confer genetic susceptibility to common subtypes of IGE. The missense mutation (Ser248Phe), associated with ADNFLE, and four silent polymorphisms in the CHRNA4 gene were genotyped in 103 IGE patients and 92 controls by polymerase chain reaction and subsequent restriction analysis. Without correction for multiple testing, the frequency of the T-allele of the silent CfoI bp595 polymorphism was increased in the entire group of IGE patients (f(T) = 0.085) compared to that in the controls (f(T) = 0.027). The allelic association was not restricted to any subgroup of IGE with either JME or idiopathic absence epilepsies. This result suggests that variation of the CHRNA4 gene, or so-far-undetected sequence variants near the CHRNA4 locus, confer susceptibility to the common IGE syndromes.

The effect of dorsal hippocampal administration of nicotinic and muscarinic cholinergic ligands on pentylenetetrazol-induced generalized seizures in rats

“…It is interesting to note, however, that previous studies point to specific cholinergic receptor subunits being important in certain forms of epilepsy [34,35,56,57], supporting the notion that multiple receptor subunits may be involved in the patterning of epileptiform activity [58].…”

Effect of nicotine and nicotinic receptors on anxiety and depression

“…Knockout mice lacking the a4 subunit of the nAChR and mice with a knockin mutation of the a4 subunit, resulting in a hypersensitive channel, show increased anxiety in the elevated plus maze and the mirrored chamber, consistent with the idea that the a4 subunit might be involved in mediating both anxiolytic and anxiogenic effects of nicotine in different conditions [73,74]. Polymorphisms in the human a4 subunit gene are not associated with panic disorder, however [75]. In addition, knockout mice lacking the b2 subunit of the nicotinic receptor were not different than wild type mice in the elevated plus maze, light dark exploration test, and mirrored chamber [76].…”

Exclusion of linkage of nine neuronal nicotinic acetylcholine receptor subunit genes expressed in brain in autosomal dominant nocturnal frontal lobe epilepsy in four unrelated families

“…Families 32 and 34 were therefore further investigated. In family 32, pairwise LOD scores between ADNFLE and informative CHRNA4 intragenic markers (CHRNA4In1STR, HgaI bp555 and CfoI bp594) [5,27] did not exclude linkage to this gene, even though LOD scores were not significant, ranging from 0.53 to 0.60 at θ = 0. Since the genomic structure of CHRNA4 was known, a mutation analysis was performed.…”

“…STRs were amplified in 12. Six CHRNA4 intragenic and a closely located extragenic (D20S20) restriction fragment length polymorphisms (RFLPs) were typed as reported [17,27]. Polymorphisms in the CHRNA5/A3/B4 cluster, due to single base pair substitutions, each occurring in one of the three genes, were characterized according to Phillips et al [20].…”