ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence

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Item Type:	Article
Title:	ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence
Creators Name:	Kubisch, C., Schmidt-Rose, T., Fontaine, B., Bretag, A.H. and Jentsch, T.J.
Abstract:	Mutations in the ClC-1 muscle chloride channel cause either recessive or dominant myotonia congenita. Using a systematic screening procedure, we have now identified four novel missense mutations in dominant (V286A, F307S) and recessive myotonia (V236L, G285E), and have analysed the effect of these and other recently described mutations (A313T, I556N) on channel properties in the Xenopus oocyte expression system. Mutations V286A, F307S and A313T displayed a 'classical' dominant phenotype: their voltage dependence was shifted towards positive potentials and displayed a dominant-negative effect by significantly imparting a voltage shift on mutant-wild-type heteromeric channels as found in heterozygous patients. In contrast, the recessive mutation V236L also shifted the voltage dependence to positive values, but co-expression with wild-type ClC-1 gave almost wild-type currents. I556N, a mutation found in patients with benign dominant myotonia, drastically shifts the voltage dependence, but only a slight shift is seen when co-expressed with wild-type ClC-1. Thus, the voltage dependence of mutant heteromeric channels is not always intermediate between those of the constituent homomeric channel subunits, a conclusion further supported by mixing different ClC-1 mutants. These complex interactions correlate clinically with various inheritance patterns, ranging from autosomal dominant with various degrees of penetrance to autosomal recessive.
Keywords:	Amino Acid Sequence, Chloride Channels, DNA Mutational Analysis, Electrophysiology, Dominant Genes, Recessive Genes, Molecular Sequence Data, Muscle Proteins, Site-Directed Mutagenesis, Mutation, Myotonia Congenita, Oocytes, Recombinant Proteins, Animals
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	7
Number:	11
Page Range:	1753-1760
Date:	October 1998
Official Publication:	http://hmg.oxfordjournals.org/cgi/content/abstract/7/11/1753
PubMed:	View item in PubMed

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