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Novel functional ε‐subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome
Author(s) -
Croxen Rebecca,
Newland Claire,
Betty Maria,
Vincent Angela,
NewsomDavis John,
Beeson David
Publication year - 1999
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/1531-8249(199910)46:4<639::aid-ana13>3.0.co;2-1
Subject(s) - congenital myasthenic syndrome , acetylcholine receptor , biology , xenopus , protein subunit , exon , messenger rna , mutation , intron , population , phenotype , endocrinology , neuromuscular transmission , microbiology and biotechnology , medicine , genetics , gene , receptor , environmental health
Acetylcholine receptor (AChR) deficiency is a recessively inherited congenital myasthenic syndrome in which fatigable muscle weakness results from impaired neuromuscular transmission caused by reduced AChR numbers. In mature muscle, AChRs consist of α 2 βδ together with the adult‐specific ε subunit. We have identified a deletion of the first nucleotide in exon 12 of the AChR ε‐subunit gene (ε1267delG) and demonstrate its recessive inheritance segregates with disease in 6 unrelated cases of AChR deficiency. In addition, we found that both healthy and AChR‐deficient muscle contain a population of AChR ε‐subunit mRNA transcripts that retain intron 11. We investigated the possible consequences of combining this mutation with the alternative mRNA species through AChR expression studies in human embryonic kidney cells and Xenopus oocytes. ε1267delG generates a polypeptide that lacks M4 and is not detected in surface AChR, whereas retention of intron 11 in the RNA transcript restores the reading frame, conserves M4, and generates a polypeptide that is incorporated into functional surface AChR, although at a reduced level, consistent with the disease phenotype. Our results indicate that for some AChR deficiency mutations located between M3 and M4, the retention of intron 11 in the ε‐subunit mRNA transcripts may rescue adult AChR function.