The dominant chloride channel mutant G200R causing fluctuating myotonia: Clinical findings, electrophysiology, and channel pathology

Wagner, Susanne; Deymeer, Feza; Kürz, Lothar L.; Benz, Sandra; Schleithoff, Lothar; Lehmann‐Horn, Frank; Serdaroğlu, Pıraye; Özdemır, Coşkun; Rüdel, Reinhardt

doi:10.1002/(sici)1097-4598(199809)21:9<1122::aid-mus2>3.0.co;2-9

Cited by 51 publications

(24 citation statements)

References 22 publications

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“…Mutant constructs contained in the expression vector pRc/CMV were used for transfection of tsA201 cells as described (18). Transient transfection was achieved using the calcium phosphate precipitation method (19) with ϳ0.01 g of plasmid DNA per 3-5 ϫ 10 3 cells/cm 2 .…”

Section: Methodsmentioning

confidence: 99%

Identification of Three Cysteines as Targets for the Zn2+ Blockade of the Human Skeletal Muscle Chloride Channel

Kürz

Klink

Jakob

et al. 1999

Journal of Biological Chemistry

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Currents through the human skeletal muscle chloride channel hClC-1 can be blocked by external application of 1 mM Zn 2؉ or the histidine-reactive compound diethyl pyrocarbonate (DEPC). The current block by Zn 2؉ strongly depends on the external pH (pK a near 6.9), whereas the block by DEPC is rather independent of the pH in the range of 5.5 to 8.5. To identify the target sites of these reagents, we constructed a total of twelve cysteine-and/or histidine-replacement mutants, transfected tsA201 cells with them, and investigated the resulting whole-cell chloride currents. The majority of the mutants exhibited a similar sensitivity toward Zn 2؉ or DEPC as wild type (WT) channels. Block by 1 mM Zn 2؉was nearly absent only with the mutant C546A. Four mutants (C242A, C254A, H180A, and H451A) were slightly less sensitive to Zn 2؉ than WT. Tests with double, triple, and quadruple mutants yielded that, in addition to C546, C242 and C254 are also most likely participating in Zn 2؉ -binding.The main chloride channel of human skeletal muscle, hClC-1, 1 is a member of the ClC chloride channel family that is unrelated to any other known ion channels (1). The first membrane topology model of ClC proteins was derived from hydropathy analysis (2); several times it had to be revised on the grounds of firmer experimental evidence (3-5). Certain mutations in the human ClC-1 gene (reviewed in Ref. 6) lead to myotonia, a disease characterized by muscle stiffness. The study of such myotonia-causing mutations provided first insights into the relationships between the primary sequence and the functions of this channel (7-10). Strong evidence suggests regions between transmembrane segments D3 and the end of D5 to participate in the pore-forming structure (11). However, these results are not in agreement with the most recently postulated topology model of ClC-1 (5). Furthermore, studies of ClC-0 (reviewed in Ref. 1), a homologous chloride channel in the electric organ of Torpedo, led to the suggestion of additional protein parts being involved in forming the ion conducting pathway.ClC channels most likely consist of two subunits (12), and in the case of ClC-0, each subunit was proposed to contain a single pore (4,13,14). Recent evidence speaks against this "doublebarreled" channel model, at least in the case of ClC-1 (15). We have found earlier that the exposure of hClC-1, stably expressed in HEK-293 cells, to 1 mM Zn 2ϩ leads to a massive reduction of the conducted chloride current (16). The results were compatible with the presence of at least two extracellularly accessible zinc-binding sites and a direct effect on ion permeation, e.g. by obstruction of the pore. The histidyl-reactive diethyl pyrocarbonate (DEPC), applied from the outside, also reduced the currents through hClC-1. The aim of this study was to identify the target residues for these blockers and, thereby, to draw inferences regarding the membrane topology and the potential location of pore-forming structures. It is known from other proteins, that Zn 2ϩ binding sites are of...

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Section: Methodsmentioning

confidence: 99%

Identification of Three Cysteines as Targets for the Zn2+ Blockade of the Human Skeletal Muscle Chloride Channel

Kürz

Klink

Jakob

et al. 1999

Journal of Biological Chemistry

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“…This disorder affects the legs much more than the arms, and has a varying severity of stiffness occurring in the ocular and masticatory muscles. 5,21 On physical examination, there is no muscle hypertrophy, but percussion and action myotonia are common. 21 Electrodiagnostically, chloride channel fluctuating myotonia produces an abundance of myotonic discharges and a CMAP amplitude that decreases after brief exercise; there is a normal response to repetitive stimulation.…”

Section: Myotonia Levior and Fluctuating Myotonia Congenitamentioning

confidence: 99%

The Nondystrophic Myotonias

Heatwole

Moxley

2007

Neurotherapeutics

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Summary:The nondystrophic myotonias are a heterogeneous set of rare diseases that demonstrate clinical myotonia, electrical myotonia, or both. These disorders are distinguished from myotonic dystrophy type 1 (DM-1), the more recently described proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM-2), and proximal myotonic dystrophy (a variant of DM-2) by characteristic clinical features, lack of abnormal nucleotide repeat expansions in the DM-1 and DM-2 genes, lack of cataracts and endocrine disturbances, and absence of significant histopathology in the muscle biopsy. The present article reviews each of the nondystrophic myotonias by exploring the unique clinical features, electrodiagnostic findings, diagnostic criteria, gene mutations, and response to pharmacologic therapy. These diseases are divided into those with chloride channel dysfunction (the myotonia congenita disorders) and those with sodium channel dysfunction (paramyotonia congenita, potassium-aggravated myotonia, and hyperkalemic periodic paralysis with myotonia). The variants that occur in each of these conditions are commented on. The differentiating features of the nondystrophic myotonias are summarized, and their predominant clinical, electrodiagnostic, and genetic characteristics are tabulated. For a comprehensive review of pertinent research and studies with application to diagnosis and treatment of individuals with nondystrophic myotonic disorders, the present article is best read in the context of other articles in this issue, especially those on ion channel physiology (Cannon) and pharmacology (Conte-Camerino), and on hyperkalemic periodic paralysis (Lehmann-Horn).

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“…The most common feature of the Cl -currents that result is a shift of the activation threshold towards more positive membrane potentials almost out of the physiological range [57,76]. As a consequence of this, the Cl -conductance is drastically reduced in the crucial vicinity of the resting membrane potential.…”

Section: Chloride Channel Myotonias Thomsen and Beckermentioning

confidence: 99%