Journal Article

ClC-1 Chloride Channel Mutations in Myotonia Congenita: Variable Penetrance of Mutations Shifting the Voltage Dependence

Christian Kubisch, Thomas Schmidt-Rose, Bertrand Fontaine, Allan H. Bretag and Thomas J. Jentsch

in Human Molecular Genetics

Volume 7, issue 11, pages 1753-1760
Published in print October 1998 | ISSN: 0964-6906
Published online October 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.11.1753
ClC-1 Chloride Channel Mutations in Myotonia Congenita: Variable Penetrance of Mutations Shifting the Voltage Dependence

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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 hetero-meric 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.

Journal Article.  5587 words.  Illustrated.

Subjects: Genetics and Genomics

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