BACKGROUND: Most congenital myasthenic syndromes (CMS) have postsynaptic defects from mutations within the muscle acetylcholine receptor (AChR). Mutations underlying the slow channel syndrome cause a "gain of function" and usually show dominant inheritance, whereas mutations underlying AChR deficiency or the fast channel syndrome cause a "loss of function" and show recessive inheritance. OBJECTIVE: To characterize the disease mechanism underlying an apparently dominantly inherited CMS that responds to IV edrophonium. METHODS: DNA from CMS patients was analyzed for mutations by single-strand conformation polymorphism analysis, DNA sequence analysis, and restriction endonuclease digestion. Functional analysis of mutations was by alpha-bungarotoxin binding studies and by patch clamp analysis of mutant AChR expressed in human embryonic kidney cells. RESULTS: Analysis of muscle biopsies from father and son in an affected kinship showed normal endplate morphology and AChR number but severely reduced miniature endplate potentials. DNA analysis revealed that each harbors a single missense mutation in the AChR alpha-subunit gene, alphaF256L. Expression studies demonstrate this mutation underlies a fast channel phenotype with fewer and shorter ion channel activations. The major effect of alphaF256L, located within the M2 transmembrane domain, is on channel gating, both reducing the opening and increasing the closure rate. CONCLUSIONS: Mutation alphaF256L results in fast channel kinetics. Expression studies suggest a dominant-negative effect within the AChR pentamer, severely compromising receptor function.
BACKGROUND: Most congenital myasthenic syndromes (CMS) have postsynaptic defects from mutations within the muscle acetylcholine receptor (AChR). Mutations underlying the slow channel syndrome cause a "gain of function" and usually show dominant inheritance, whereas mutations underlying AChR deficiency or the fast channel syndrome cause a "loss of function" and show recessive inheritance. OBJECTIVE: To characterize the disease mechanism underlying an apparently dominantly inherited CMS that responds to IV edrophonium. METHODS: DNA from CMS patients was analyzed for mutations by single-strand conformation polymorphism analysis, DNA sequence analysis, and restriction endonuclease digestion. Functional analysis of mutations was by alpha-bungarotoxin binding studies and by patch clamp analysis of mutant AChR expressed in human embryonic kidney cells. RESULTS: Analysis of muscle biopsies from father and son in an affected kinship showed normal endplate morphology and AChR number but severely reduced miniature endplate potentials. DNA analysis revealed that each harbors a single missense mutation in the AChR alpha-subunit gene, alphaF256L. Expression studies demonstrate this mutation underlies a fast channel phenotype with fewer and shorter ion channel activations. The major effect of alphaF256L, located within the M2 transmembrane domain, is on channel gating, both reducing the opening and increasing the closure rate. CONCLUSIONS: Mutation alphaF256L results in fast channel kinetics. Expression studies suggest a dominant-negative effect within the AChR pentamer, severely compromising receptor function.
Authors: Hakan Cetin; Max Epstein; Wei W Liu; Susan Maxwell; Pedro M Rodriguez Cruz; Judith Cossins; Angela Vincent; Richard Webster; Philip C Biggin; David Beeson Journal: Proc Natl Acad Sci U S A Date: 2019-09-30 Impact factor: 11.205
Authors: Lisa Denning; Jennifer A Anderson; Ryan Davis; Jeffrey P Gregg; Jennifer Kuzdenyi; Ricardo A Maselli Journal: PLoS One Date: 2007-09-19 Impact factor: 3.240