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

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Item Type:	Article
Title:	Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice
Creators Name:	Gronemeier, M., Condie, A., Prosser, J., Steinmeyer, K., Jentsch, T.J. and Jockusch, H.
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.
Keywords:	Amino Acid Sequence, Base Sequence, Chloride Channels, Complementary DNA, Molecular Sequence Data, Muscles, Mutation, Myotonia, Amino Acid Sequence Homology, Animals, Mice
Source:	Journal of Biological Chemistry
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	269
Number:	8
Page Range:	5963-5967
Date:	25 February 1994
Official Publication:	http://www.jbc.org/content/269/8/5963.abstract
PubMed:	View item in PubMed

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