Muscle channelopathies and critical points in functional and genetic studies
Karin Jurkat-Rott, Frank Lehmann-Horn
Karin Jurkat-Rott, Frank Lehmann-Horn
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2000-2009. https://doi.org/10.1172/JCI25525.
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Muscle channelopathies and critical points in functional and genetic studies

Abstract

Muscle channelopathies are caused by mutations in ion channel genes, by antibodies directed against ion channel proteins, or by changes of cell homeostasis leading to aberrant splicing of ion channel RNA or to disturbances of modification and localization of channel proteins. As ion channels constitute one of the only protein families that allow functional examination on the molecular level, expression studies of putative mutations have become standard in confirming that the mutations cause disease. Functional changes may not necessarily prove disease causality of a putative mutation but could be brought about by a polymorphism instead. These problems are addressed, and a more critical evaluation of the underlying genetic data is proposed.

Authors

Karin Jurkat-Rott, Frank Lehmann-Horn

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Figure 3

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ClC-1, the major chloride channel of skeletal muscle. A membrane topolog...
ClC-1, the major chloride channel of skeletal muscle. A membrane topology model of the ClC-1 monomer is shown. X-ray measurements and cryo-electron microscopy have elucidated the structure of the channel (104, 105) and confirmed the conclusions derived from electrophysiological results. The functional channel is an antiparallel assembled homodimer. It possesses 2 independent ion-conducting pores, each with a fast-opening mechanism of its own, 2 selectivity filters, and 2 voltage sensors (106). The channel is functional without any other subunits. Symbols are used for the mutations leading to either dominant myotonia congenita (DMC) or recessive myotonia congenita (RMC). The amino acids at which substitutions occur are indicated by 1-letter abbreviations and numbered according to the protein sequence. Adapted with permission from Nature (104).