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Journal Article| Volume 269, ISSUE 8, P5963-5967, February 25, 1994

Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice.

Open AccessPublished:February 25, 1994DOI:https://doi.org/10.1016/S0021-9258(17)37556-7
Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice.
Previous ArticleAn in-frame deletion of codon 298 of the NADH-cytochrome b5 reductase gene results in hereditary methemoglobinemia type II (generalized type). A functional implication for the role of the COOH-terminal region of the enzyme.
Next ArticleIdentification of a human CD36 isoform produced by exon skipping. Conservation of exon organization and pre-mRNA splicing patterns with a CD36 gene family member, CLA-1.
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      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.

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      Published online: February 25, 1994

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      DOI: https://doi.org/10.1016/S0021-9258(17)37556-7

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