CHRNE – Congenital Myasthenic Syndrome

CHRNE encodes the ε-subunit of the adult acetylcholine receptor (AChR) at the neuromuscular junction. Mutations in CHRNE lead to autosomal recessive congenital myasthenic syndrome (CMS) characterized by impaired endplate AChR density or kinetic abnormalities, manifesting as fatigable muscle weakness, ptosis, and ophthalmoplegia.

Extensive genetic studies have identified CHRNE variants in 33 unrelated probands, including 10 novel alleles, through whole-exome sequencing of an Iranian CMS cohort ([PMID:39550999]). Recurrent frameshift mutations such as c.1327del (p.Glu443LysfsTer64) were observed in four families, and c.1252_1267dup (p.Cys423fs) in three families, supporting autosomal recessive inheritance and strong gene–disease correlation.

The variant spectrum includes early truncating frameshift and splice-site mutations leading to primary AChR deficiency, as well as missense changes causing slow-channel kinetic defects. A founder truncating mutation, ε1293insG (c.1248_1266dup (p.Cys423fs)), accounts for ~60% of North African cases, indicating population-specific alleles ([PMID:19064877]).

Functional assays demonstrate that truncating CHRNE mutations reduce AChR levels and impair end-plate maturation, with ultrastructural evidence of immature synaptic folds and utrophin deficiency ([PMID:11030414]). Alternative splicing retaining intron 11 can partially rescue receptor assembly in vitro ([PMID:10514102]). Slow-channel mutations (e.g., p.Leu289Phe) prolong channel opening and respond to combined fluoxetine and salbutamol therapy ([PMID:27779167]).

Clinically, CMS due to CHRNE mutations presents at birth or early infancy with bilateral ptosis (HP:0000508), ophthalmoplegia (HP:0000602), and generalized muscle weakness (HP:0003324). Most patients benefit from cholinesterase inhibitors, and β2-adrenergic agonists provide additional improvement in refractory cases.

References

• Neuromuscular disorders : NMD • 2025 • CHRNE-related congenital myasthenic syndrome in Iran: Clinical and molecular insights. PMID:39550999
• Neurology • 2008 • The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. PMID:19064877
• Human genetics • 2000 • Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations. PMID:11030414
• Annals of neurology • 1999 • Novel functional epsilon-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome. PMID:10514102
• Chinese medical journal • 2016 • A Missense Mutation in Epsilon-subunit of Acetylcholine Receptor Causing Autosomal Dominant Slow-channel Congenital Myasthenic Syndrome in a Chinese Family. PMID:27779167

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