CHRNB2 – Sleep-related Hypermotor Epilepsy

CHRNB2 encodes the β2-subunit of the neuronal nicotinic acetylcholine receptor (nAChR), critical for cholinergic neurotransmission in cortical and thalamic circuits. Pathogenic variants in CHRNB2 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy, now classified under sleep-related hypermotor epilepsy (SHE) (MONDO:0000030).

Several case reports have identified heterozygous missense mutations in CHRNB2 associated with typical SHE. A de novo c.936C>G (p.Ile312Met) variant in the M3 transmembrane region was found in monozygotic twins presenting SHE with prominent memory deficits and increased ACh sensitivity (PMID:15964197). In a tertiary referral series, a c.859G>A (p.Val287Met) variant was detected in one of eight probands with familial SHE (PMID:35177946).

CHRNA4 and CHRNB2 TM3 mutations have been reported in three unrelated families, each showing autosomal dominant segregation with at least three additional affected relatives harboring either p.Val287Met or p.Val308Ala variants (PMID:18456869). Collectively, these genetic data encompass four unrelated probands and confirm AD inheritance with cosegregation.

Functional electrophysiological assays of CHRNB2 TM3 mutants (p.Ile312Met, p.Val287Met, p.Val308Ala) demonstrate a consistent gain-of-function mechanism, characterized by increased acetylcholine potency, enhanced channel open probability, and altered pharmacogenomic profiles in heterologous systems (PMID:18456869). These findings recapitulate the hyperexcitability observed in human SHE.

A variant c.77C>T (p.Thr26Met) in CHRNB2 was reported in a patient with predominantly sleep-related insular epilepsy but lacks segregation data and clear phenotypic concordance, limiting its current classification (PMID:32536355).

Overall, CHRNB2 meets a Moderate level of clinical validity for SHE based on multiple probands, familial segregation, and mechanistic functional concordance. Additional large pedigrees and in vivo models would further strengthen this association. Key take-home: CHRNB2 gain-of-function variants should be included in genetic testing panels for SHE to inform diagnosis, genetic counseling, and targeted treatment strategies.

References

• Neurobiology of disease • 2005 • The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits. PMID:15964197
• Journal of central nervous system disease • 2022 • Sleep-related hypermotor epilepsy with genetic diagnosis: description of a case series in a tertiary referral hospital. PMID:35177946
• Molecular pharmacology • 2008 • Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore. PMID:18456869
• The Canadian journal of neurological sciences • 2020 • Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy. PMID:32536355

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