Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy

Abstract

Purpose: Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy. Method: We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77C>T; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079G>A; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77C>T) in the CHRNB2 gene. Results: We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4β2 (wild-type), α4β2-Thr26Met (homozygote), and α4β2/β2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation. Conclusions: This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

“…The expression and prognosis of TUBB2A [399], PAK1 [400], PRKCG (protein kinase C gamma) [401], CACNA1G [402], ATP1A3 [403] and KCNJ10 [404] have been investigated in ataxia. SCN3B [405], PCDH19 [406], CNTNAP2 [407], STXBP1 [408], CHRNB2 [409], NAPA (NSF attachment protein alpha) [410], STX1B [411], GABRG2 [412], CAMKK2 [144], CNTNAP2 [413], ARHGEF9 [414], COX8A [415], CALHM1 [416], SLC45A1 [417], TLR5 [418] and KCNJ10 [419] could be acuseful prognostic biomarker in epilepsy. The altered expression of NPTX2 [420], VAMP2 [421], PRKAR1B [422], SNCB (synuclein beta) [199], AP2M1 [423], TUBA4A [424], KIF17 [425] and SYK (spleen associated tyrosine kinase) [426] might be related to the progression of dementia.…”

Cholinergic Signaling, Neural Excitability, and Epilepsy

“…Additionally, an increase of midbrain nAChRs density could be involved in the pathological of ADSHE through the brainstem cholinergic signaling in the ascending arousal system [ 56 ]. A study of ADSHE variants in CHRNB2 and CHRNA4 closely relevant to patients with insular epilepsy recently, CHRNB2 and CHRNA4 increased nicotinic currents in whole-cell recording [ 57 ]. In addition, clinical data demonstrated that mutations in CHRNA4 may be a novel gene causing genetic or focal epilepsy with febrile seizures [ 58 ] and familial partial epilepsy with variable foci [ 59 ], it aims to broaden the genotypic-phenotypic spectrum of combined epileptic in CHRNA4 .…”

“…[56] Patients with insular epilepsy Interictal period Mutant nACh receptors increased nicotinic currents in whole-cell recording. [57] Genetic or focal epilepsy with febrile seizures (GEFS+) patients…”

Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology

“…ADSHE-linked mutations were soon also found on CHRNB2 [46,47], and the number of ADSHE mutations found on CHRNA4 or CHRNB2 has subsequently increased at a steady pace [19,48,49]. Recently, variants of heteromeric nAChR subunits have been also suggested to be implicated in other epileptic forms [50][51][52]. In contrast, despite the wide expression of α7 receptors in the brain [30], evidence about the involvement of CHRNA7 in epilepsy is weak.…”