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

Abstract

Members of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) gene family ( CHRNA4 and CHRNB2, coding for the alpha4 and beta2 subunits, respectively) are involved in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). However, ADNFLE is genetically heterogeneous and mutations in CHRNA4 and CHRNB2 account for only a minority of ADNFLE cases. Additional nAChR subunits expressed in the brain are candidates for this epilepsy. The involvement of all genes coding for brain-expressed nAChR subunits, with known chromosome localization ( CHRNB2, 1q21; CHRNA2, 8p21; CHRNA6, CHRNB3, 8p11.2; CHRNA7, 15q14; CHRNA5/A3/B4, 15q24 and CHRNA4, 20q13.2) was investigated in four unrelated ADNFLE Italian families for at least three generations. Families were selected on the basis of anamnestic and videopolysomnographic analyses. Individuals were typed for polymorphic markers located in the above mentioned chromosome regions. Linkage and mutation analyses were performed. In none of the families was linkage between ADNFLE and the analysed chromosome regions detected. These findings support the hypothesis that genes different from those coding for alpha2-7 and beta2-4 neuronal nAChR subunits could be responsible for ADNFLE.

Autosomal dominant nocturnal frontal lobe epilepsy

“…However, as reported above, there are still a number of open questions concerning their role in the pathogenesis of the disease. Moreover, very recently we have shown that in four Italian families from our sample, none of the brain-expressed nAChR subunit genes so far identified and mapped on the human genome is associated with ADNFLE [11]. This finding points to the existence of at least a fourth locus for ADNFLE and/or to the involvement of new genes not belonging to the nAChR gene family or of yet unidentified brain-expressed nAChR genes in the pathogenesis of the disease.…”

“…The existence of three different loci for ADNFLE together with the recently reported suggestion of a fourth locus (different from nAChR subunit genes) [11], could be explained by considering ADNFLE as a monogenic disease in which a single mutation in one of the genes involved in the same neuronal network/s of nAChR is responsible for the phenotype. However, a different hypothesis could be put forward.…”

“…In their work, however, they searched for additional mutations only in the remaining nAChR subunit genes. Because it has recently been reported that no nAChR subunit is involved in the pathogenesis of ADNFLE in four Italian families [11], which suggests the involvement of new genes not belonging to the nAChR subunit family, it would probably be better to perform a genome-wide search for new candidate genes. The strategy adopted by many authors to identify mutations in ADNFLE families was to search for the presence of linkage and of mutation only in the two known ADNFLE genes (CHRNA4 and CHRNB2).…”

DNA methylation in neonates born to women receiving psychiatric care

“…30,31 CHRNA2 is a broadly-expressed subunit of nicotinic acetylcholine receptors. 32 In addition to its role in nicotine dependence and neurocognitive functioning, 33,34 CHRNA2 is located in a region of chromosome 8p that is suggested to contribute to psychiatric and neurodegenerative disorders. 35 Interestingly, nominal differential methylation of CHRNA2 was recently reported in monozygotic twins discordant for psychosis.…”

Genetic basis in epilepsies caused by malformations of cortical development and in those with structurally normal brain

“…A third locus for a yet unidentified gene exist on chromosome 15q24 . The presence of a fourth locus is likely since some families do not show linkage to any of the known loci (Bonati et al 2002;Derry et al 2008). Neuronal nicotic acetylcholine receptors are mostly presynaptic channels playing a role in the regulation of excitatory neurotransmitters.…”