ArticleThe Journal of physiology2012
Disease-causing mutations C277R and C277Y modify gating of human ClC-1 chloride channels in myotonia congenita.
Article in The Journal of physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed.
- Clinical and molecular characterization of myotonia congenita using whole-exome sequencing in Egyptian patients.Molecular biology reports · 2024Article
- ClC-1 Chloride Channel: Inputs on the Structure-Function Relationship of Myotonia Congenita-Causing Mutations.Biomedicines · 2023Review
- Case report: Incomplete penetrance of autosomal dominant myotonia congenita caused by a rareFrontiers in genetics · 2022Article
- Chaperone activity of niflumic acid on ClC-1 chloride channel mutants causing myotonia congenita.Frontiers in pharmacology · 2022Article
- Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy.Cells · 2021Review
- Functional analysis of the F337C mutation in the CLCN1 gene associated with dominant myotonia congenita reveals an alteration of the macroscopic conductance and voltage dependence.Molecular genetics & genomic medicine · 2021Article
- Skeletal muscle ClC-1 chloride channels in health and diseases.Pflugers Archiv : European journal of physiology · 2020Review
- Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita.Frontiers in neurology · 2020Review
- Article
- FKBP8 Enhances Protein Stability of the CLC-1 Chloride Channel at the Plasma Membrane.International journal of molecular sciences · 2018Article
- A Cyclic Nucleotide-Gated Channel, HvCNGC2-3, Is Activated by the Co-Presence of Na⁺ and K⁺ and Permeable to Na⁺ and K⁺ Non-Selectively.Plants (Basel, Switzerland) · 2018Article
- Reduced Membrane Insertion of CLC-K by V33L Barttin Results in Loss of Hearing, but Leaves Kidney Function Intact.Frontiers in physiology · 2017Article
- ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies.Frontiers in pharmacology · 2017Review
- Multidisciplinary study of a new ClC-1 mutation causing myotonia congenita: a paradigm to understand and treat ion channelopathies.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.Scientific reports · 2016Article
- Carboxyl-terminal Truncations of ClC-Kb Abolish Channel Activation by Barttin Via Modified Common Gating and Trafficking.The Journal of biological chemistry · 2015Article
- Impaired surface membrane insertion of homo- and heterodimeric human muscle chloride channels carrying amino-terminal myotonia-causing mutations.Scientific reports · 2015Article
- ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation.The Journal of physiology · 2015Article
- Clinical, Molecular, and Functional Characterization of CLCN1 Mutations in Three Families with Recessive Myotonia Congenita.Neuromolecular medicine · 2015Article
- The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels.Scientific reports · 2015Article
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Abstract
Myotonia congenita is a genetic condition that is caused by mutations in the muscle chloride channel gene CLCN1 and characterized by delayed muscle relaxation and muscle stiffness. We here investigate the functional consequences of two novel disease-causing missense mutations, C277R and C277Y, using heterologous expression in HEK293T cells and patch clamp recording. Both mutations reduce macroscopic anion currents in transfected cells. Since hClC-1 is a double-barrelled anion channel, this reduction in current amplitude might be caused by altered gating of individual protopores or of joint openings and closing of both protopores. We used non-stationary noise analysis and single channel recordings to separate the mutants' effects on individual and common gating processes. We found that C277Y inverts the voltage dependence and reduces the open probabilities of protopore and common gates resulting in decreases of absolute open probabilities of homodimeric channels to values below 3%. In heterodimeric channels, C277R and C277Y also reduce open probabilities and shift the common gate activation curve towards positive potentials. Moreover, C277Y modifies pore properties of hClC-1. It reduces single protopore current amplitudes to about two-thirds of wild-type values, and inverts the anion permeability sequence to I(-) = NO(3)(-) >Br(-)>Cl(-). Our findings predict a dramatic reduction of the muscle fibre resting chloride conductance and thus fully explain the disease-causing effects of mutations C277R and C277Y. Moreover, they provide additional insights into the function of C277, a residue recently implicated in common gating of ClC channels.
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