title: F413C and A531V but not R894X myotonia congenita mutations cause defective endoplasmic reticulum export of the muscle-specific chloride channel CLC-1.
abstract: In northern Finland myotonia congenita is caused by three main mutations in the ClC-1 chloride channel. We studied the molecular basis of these mutations (1238T>G/F413C, 1592C>T/A531V, and 2680C>T/R894X). The mutated cDNAs were expressed either in L6 myotubes or in isolated rat myofibers using recombinant Semliki Forest virus. Experiments in L6 cells indicated that A531V and R894X proteins suffered from stability problems in these cells. Analysis in myofibers indicated that the A531V protein was totally retained in the endoplasmic reticulum (ER), whereas the export of the F413C protein was severely reduced. The C-terminal nonsense mutant (R894X), however, was normally transported to the Golgi elements in the myofibers. Defective export or reduced stability of the mutated proteins may thus be reasons for the myotonic symptoms.
authors.affiliation: Department of Anatomy and Cell Biology, University of Oulu, PO Box 5000, Oulu FI-90014, Finland. hinni.papponen@oulu.fi
authors.forename: Hinni
authors.initials: H
authors.lastname: Papponen
authors.forename: Marja
authors.initials: M
authors.lastname: Nissinen
authors.forename: Tuula
authors.initials: T
authors.lastname: Kaisto
authors.forename: Vilho V
authors.initials: VV
authors.lastname: Myllylä
authors.forename: Raili
authors.initials: R
authors.lastname: Myllylä
authors.forename: Kalervo
authors.initials: K
authors.lastname: Metsikkö
mesh_terms: D000409:Alanine / Q000235:genetics; D000596:Amino Acids / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000235:genetics; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism*; D020756:Coatomer Protein / Q000378:metabolism; D003545:Cysteine / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D032342:Muscle Cells / Q000648:ultrastructure*; D009124:Muscle Proteins / Q000378:metabolism; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010649:Phenylalanine / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection / Q000379:methods; D014633:Valine / Q000235:genetics
chemical_list: D000596:Amino Acids; C086321:CLC-1 channel; D018118:Chloride Channels; D020756:Coatomer Protein; D009124:Muscle Proteins; D016376:Oligonucleotides, Antisense; D010649:Phenylalanine; D001120:Arginine; D014633:Valine; D003545:Cysteine; D000409:Alanine