title: Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice.
abstract: In mature vertebrate muscle, the chloride channel Clc-1 is necessary for the stabilization of the resting potential. Its functional defect leads to the disease myotonia. The ADR mouse (phenotype ADR, genotype adr/adr) is an animal model for human myotonias. The adr gene is a member of a family of non-complementing recessive autosomal mutations ("alleles" of adr) that cause myotonia in the mouse. The standard allele adr has arisen by the insertion of a retroposon into the chloride channel gene Clc-1 (Steinmeyer, K., Klocke, R., Ortland, C., Gronemeier, M., Jockusch, H., Gründer, S., and Jentsch, T. J. (1991) Nature 354, 304-308). In order to study the nature of two other alleles, adrmto and adrK, we have analyzed overlapping Clc-1 cDNA amplification products by the hydroxylamine and osmium tetroxide modification technique and direct sequencing. A comparison between ADR*MTO and C57BL/6 wild type showed six base pair substitutions, one of which resulted in a stop codon in position 47, whereas the five others are either silent or lead to amino acid substitutions in non-conserved regions of the Clc-1 sequence and were already present in the wild type inbred SWR/J strain from which adrmto was derived. The detection of the stop codon in the adrmto allele is further indication of the identity of the Clc-1 chloride channel with the adr myotonia gene in the mouse, because a chain termination close to the N terminus would necessarily destroy gene function. For the ethylnitrosourea-induced mutation adrK, an Ile-->Thr exchange in codon 553 was identified. As this affects a conserved residue within a highly conserved region of the Clc-1 gene, a functional significance of this residue is suggested.
authors.affiliation: Developmental Biology Unit, University of Bielefeld, Federal Republic of Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gronemeier
authors.forename: A
authors.initials: A
authors.lastname: Condie
authors.forename: J
authors.initials: J
authors.lastname: Prosser
authors.forename: K
authors.initials: K
authors.lastname: Steinmeyer
authors.forename: T J
authors.initials: TJ
authors.lastname: Jentsch
authors.forename: H
authors.initials: H
authors.lastname: Jockusch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018118:Chloride Channels / Q000235:genetics*; D018076:DNA, Complementary; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism*; D009154:Mutation; D009222:Myotonia / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D018118:Chloride Channels; D018076:DNA, Complementary