A Mutation in Autosomal Dominant Myotonia Congenita Affects Pore Properties of the Muscle Chloride Channel

Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl-channel gene (CLCN1, 7q35). Here, we report that a mutation predicting the substitution of Gly 230 by glutamic acid (G230E) between segments D3 and D4 dramatically alters the p...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-03, Vol.94 (6), p.2729-2734
Main Authors: Fahlke, Christoph, Beck, Carol L., George, Alfred L.
Format: Article
Language:English
Subjects:
Anions
Binding sites
Biological Sciences
Cell Line
Cell lines
Chloride Channels - genetics
Chloride Channels - physiology
Chromosome Mapping
Chromosomes, Human, Pair 7
Disease
Electric potential
Genes
Genes, Dominant
Genetic mutation
Humans
Iodides
Iodides - pharmacology
Ions
Membrane Potentials - drug effects
Muscle, Skeletal - physiopathology
Muscular system
Mutation
Myotonia congenita
Myotonia Congenita - genetics
Myotonia Congenita - physiopathology
Patch-Clamp Techniques
Point Mutation
Recombinant Proteins - metabolism
Time constants
Time Factors
Transfection
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Summary:Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl-channel gene (CLCN1, 7q35). Here, we report that a mutation predicting the substitution of Gly 230 by glutamic acid (G230E) between segments D3 and D4 dramatically alters the pore properties of a recombinant human muscle Cl-channel (hClC-1) expressed in a mammalian cell line (tsA201). The G230E mutation causes substantial changes in anion and cation selectivity as well as a fundamental change in rectification of the current-voltage relationship. Whereas wild-type channels are characterized by pronounced inward rectification and a Cl > thiocyanate > Br > NO3> I > CH3SO3selectivity, G230E exhibits outward rectification at positive potentials and a thiocyanate > NO3> I > Br > Cl > CH3SO3selectivity. Furthermore, the cation-to-anion permeability ratio of the mutant is much greater than that of the wild-type channel. Voltage-dependent blocks by intracellular and extracellular iodide help to distinguish two distinct ion binding sites within the hClC-1 conduction pathway. Both binding sites are preserved in the mutant but have decreased affinities for iodide. These findings suggest that Gly 230 is critical for normal ion conductance in hClC-1 and that this residue resides within the channel pore.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.6.2729