CHRNA2 – Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a sleep-related hypermotor epilepsy characterized by clusters of brief nocturnal seizures arising from the frontal cortex. CHRNA2 (HGNC:1956) encodes the α2 subunit of the neuronal nicotinic acetylcholine receptor and has emerged as a rare genetic cause of ADNFLE. Mutations in CHRNA4 and CHRNB2 account for the majority of familial cases, but recent evidence implicates CHRNA2 in a subset of patients.

Two unrelated probands have been reported with heterozygous CHRNA2 missense mutations. One patient harbored c.754T>C (p.Tyr252His) inherited from the mother, identified by Sanger sequencing of all CHRNA2 coding exons (1 proband) (PMID:30809122). A second large ADNFLE pedigree carried c.889A>T (p.Ile297Phe) segregating in six living affected individuals across three generations (6 affected relatives) (PMID:25770198).

Functional assays in HEK293 cells demonstrated that α2(p.Tyr252His) co-expressed with either β2 or β4 subunits reduced maximal nicotine-evoked currents by ~80% and caused a tenfold decrease in epibatidine binding affinity without altering receptor expression (PMID:30809122). Similarly, α2(p.Ile297Phe) exhibited a 60% reduction in whole-cell current density in heterozygous configuration and abolished currents in homozygosity, confirming a loss-of-function mechanism concordant with clinical phenotype (PMID:25770198).

Multiple linkage and mutation screens in cohorts and families failed to detect pathogenic CHRNA2 variants in 4 Italian pedigrees (PMID:12195439), 47 families (PMID:17602836), three ADNFLE kindreds (PMID:17324557), and 257 Chinese patients (PMID:26309560), indicating genetic heterogeneity and a low prevalence of CHRNA2-related ADNFLE.

Taken together, CHRNA2 meets moderate clinical validity for ADNFLE based on two probands (one segregating in a six-member family) with concordant in vitro loss-of-function data. Further large-scale sequencing will clarify prevalence across populations. Routine genetic testing for CHRNA2 variants can inform diagnosis, familial risk assessment, and potential targeted therapies.

Key Take-home: CHRNA2 loss-of-function mutations are an uncommon but clinically actionable cause of autosomal dominant nocturnal frontal lobe epilepsy.

References

• Frontiers in molecular neuroscience • 2019 • CHRNA2 and Nocturnal Frontal Lobe Epilepsy: Identification and Characterization of a Novel Loss of Function Mutation. PMID:30809122
• Neurology • 2015 • Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. PMID:25770198
• Journal of neurology • 2002 • 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. PMID:12195439
• Neuroscience letters • 2007 • A major role of the nicotinic acetylcholine receptor gene CHRNA2 in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is unlikely. PMID:17602836
• Epilepsy research • 2007 • Further evidence of genetic heterogeneity in families with autosomal dominant nocturnal frontal lobe epilepsy. PMID:17324557
• International journal of clinical and experimental medicine • 2015 • Mutational analysis of CHRNB2, CHRNA2 and CHRNA4 genes in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy. PMID:26309560

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