CHRNA1 – Congenital Myasthenic Syndrome

CHRNA1 encodes the muscle nicotinic acetylcholine receptor (AChR) α1 subunit, critical for neuromuscular transmission. Pathogenic CHRNA1 variants cause congenital myasthenic syndrome (CMS; MONDO:0018940), characterized by fatigable skeletal muscle weakness, ptosis (HP:0000508), and external ophthalmoplegia (HP:0000544). Initial kinetic abnormalities of AChR were reported in siblings presenting poor suck and ocular fatigability, consistent with fast-channel CMS ([PMID:7685992]).

Genetic studies have identified both autosomal recessive and autosomal dominant CHRNA1 variants in CMS. Recessive loss-of-function alleles (nonsense, frameshift, splice) lead to AChR deficiency at endplates, whereas dominant missense variants alter channel kinetics. A notable heterozygous missense mutation, c.757T>G (p.Phe253Val), disrupts gating speeds, whereas c.823G>A (p.Val275Met) has been associated with gain-of-function fast-channel phenotypes ([PMID:31570625]).

Segregation analysis in affected families supports pathogenicity: the original pedigree included a propositus and an affected sister, demonstrating familial cosegregation of the CHRNA1 kinetic abnormality ([PMID:7685992]). Additional unrelated probands harboring heterozygous kinetic variants further strengthen the gene–disease link.

Functional assays corroborate the disease mechanism. The slow-channel CMS mutation c.1314C>G (p.Cys438Trp) in the M4 domain increases the channel open-state stability, prolonging synaptic currents. Allele-specific siRNA selectively silenced the mutant transcript, restoring normal channel kinetics in vitro ([PMID:16685696]).

No studies to date have refuted the CHRNA1–CMS association. The concordance of genetic, segregation, and functional data across multiple independent families establishes a strong causal relationship.

Integrating these data supports a strong ClinGen gene–disease validity classification. CHRNA1 variant analysis informs diagnosis, guides family counseling, and enables targeted therapies such as allele-specific knockdown. Key take-home: CHRNA1 variants underlie both loss- and gain-of-function CMS, and functional assays are essential for precise therapeutic strategies.

References

• Annals of Neurology • 1993 • Newly recognized congenital myasthenic syndrome associated with high conductance and fast closure of the acetylcholine receptor channel. PMID:7685992
• Proceedings of the National Academy of Sciences of the United States of America • 2019 • Muscle acetylcholine receptor conversion into chloride conductance at positive potentials by a single mutation. PMID:31570625
• Annals of Neurology • 2006 • Slow-channel mutation in acetylcholine receptor alphaM4 domain and its efficient knockdown. PMID:16685696

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