The acetylcholine (nicotinic cholinergic) receptor protein comprises of 1 beta, 1 gamma, 1 delta, and 2 alpha subunits. CHRNB1 encodes the beta subunit of the receptor which functions on the postsynaptic side of the neuromuscular junction. Acetylcholine binds these receptors and activates membrane ion channel pores on the motor end plate, mediating electric signaling between nerve and muscle cells.
Defective CHRNB1 has been associated with slow-channel myasthenic syndrome 2A and 2C. Myasthenia syndromes are characterized by extended acetylcholine receptor activity, prolonged motor endplate currents, and cationic overload. These factors result in motor endplate myopathy as well as remodeling of the post-synaptic membrane and degeneration of folds at the neuromuscular junction.
CHRNB1 is located on the p arm of chromosome 17 and is 12,647 bases long, ranging from position 7,445,061 to 7,457,707 base pairs pter. It contains 11 exons and translates into a 501aa long protein with a molecular weight of 56,698 Da. CHRNB1 mRNA is expressed in all tissues and is most abundant in skeletal muscle followed by glandular tissues; protein is overexpressed in testis. 1 alternately spliced isoform as well as 12 paralog genes exist.
Heterozygous as well as compound heterozygous mutations in CHRNB1 have been associated with slow-channel myasthenic syndrome 2A and 2C respectively. Mutations consist of missense, deletion, and nonsense variants; these variants are thought to remodel the post-synaptic acetylcholine receptor, prolonging activity of the receptor and slowing the rate of receptor closure, resulting in endplate myopathy. Other mutations have been shown to disrupt acetylcholine receptor assembly by directly affecting subunit interactions.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were likely pathogenic, 1 patient was diagnosed with congenital myasthenic syndrome 2A. A previously reported de novo heterozygous missense transition in CHRNB1 (c.865G>A, p.Val289Met) was identified as the probable cause.
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