CHRNB2 – Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by sleep-related hypermotor seizures arising from frontal lobe foci, often with variable drug response and neuropsychiatric comorbidities. CHRNB2 encodes the β2-subunit of the neuronal nicotinic acetylcholine receptor, a heteromeric channel modulating cortical excitability. Pathogenic CHRNB2 variants were among the first genetic causes identified for ADNFLE following mutational screening in Italian probands PMID:11952766. These mutations have expanded the spectrum of nicotinic receptor gene defects in ADNFLE alongside CHRNA4 and CHRNA2. The association between CHRNB2 and ADNFLE is supported by multiple familial reports with segregation and supportive functional data, satisfying criteria for a Strong gene–disease relationship.

Two CHRNB2 missense variants, c.859G>T (p.Val287Leu) and c.923T>C (p.Val308Ala), have been reported in three unrelated ADNFLE families, segregating with disease in 16 affected individuals PMID:22897520PMID:18456869. In an Italian pedigree with hippocampal sclerosis, the c.859G>T (p.Val287Leu) variant co-segregated in 10 affected members presenting nocturnal hypermotor seizures and refractory epilepsy in one individual PMID:22897520. The c.923T>C (p.Val308Ala) and an additional V287M (c.859G>A, p.Val287Met) mutation were identified in three families of Turkish Cypriot, Scottish, and English origin, evidencing recurrent TM3 mutations beyond founder effects PMID:18456869.

Conversely, mutational screening of 24 Italian ADNFLE probands for exon 5 of CHRNB2 revealed no pathogenic variants, underscoring the rarity of CHRNB2 mutations in sporadic cases PMID:11952766. This limited detection rate suggests locus heterogeneity and points to additional monogenic or digenic contributors in ADNFLE.

Electrophysiological characterization of CHRNB2 TM2 and TM3 mutants demonstrated gain-of-function with increased acetylcholine sensitivity, elevated open probability, and enhanced macroscopic currents. TM3 mutations (Val308Ala, Val287Met) recapitulate the gating defects observed in classical TM2 variants, confirming a shared pathomechanism of channel hypersensitivity PMID:18456869. Such functional assays provide moderate-level evidence aligning receptor dysfunction with the human seizure phenotype.

Although CHRNB2 variants establish a strong association with ADNFLE, some pedigrees lack CHRNB2 mutations despite linkage to the ENFL3 locus, indicating genetic heterogeneity. The modest mutation frequency and absence of large-scale segregation data beyond primary families limit a definitive classification in sporadic cohorts.

In sum, CHRNB2 gain-of-function mutations in transmembrane regions are robustly linked to autosomal dominant nocturnal frontal lobe epilepsy, substantiated by familial segregation, functional concordance, and recurrent alleles. Genetic testing of CHRNB2 should be considered in ADNFLE patients, particularly when seizures are refractory or hippocampal sclerosis is present. Incorporation of CHRNB2 variant analysis enhances molecular diagnosis and informs tailored therapeutic strategies. Key take-home: CHRNB2 mutations, notably c.859G>T (p.Val287Leu), are actionable diagnostic markers in ADNFLE.

References

• European journal of neurology • 2013 • Hippocampal sclerosis worsens autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) phenotype related to CHRNB2 mutation. PMID:22897520
• 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
• Epilepsia • 2002 • Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy. PMID:11952766

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