Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia

Altamura, Concetta; Иванова, Е. А.; Imbrici, Paola; Conte, Elena; Camerino, Claudia; Дадали, Е. Л.; Polyakov, A. V.; Kurbatov, S. V.; Girolamo, Francesco; Carratù, Maria Rosaria; Desaphy, Jean-François

doi:10.3389/fneur.2020.01019

Cited by 6 publications

(9 citation statements)

References 36 publications

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“…It is worth noting that a number of trafficking-defective ClC-1 channels might remain functionally inactive once rescued to the plasma membrane. For instance, the G411C mutation disrupted the folding of the ClC-1 protein, making the chloride channels both trafficking-defective and nonfunctional ( Altamura et al, 2020b ). In this case, the drug should be able to not only restore cell surface expression but also improve channel functions.…”

Section: Discussionmentioning

confidence: 99%

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Chaperone activity of niflumic acid on ClC-1 chloride channel mutants causing myotonia congenita

et al. 2022

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Myotonia congenita (MC) is an inherited rare disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. It is caused by loss-of-function mutations in the skeletal muscle chloride channel ClC-1, important for the stabilization of resting membrane potential and for the repolarization phase of action potentials. Thanks to in vitro functional studies, the molecular mechanisms by which ClC-1 mutations alter chloride ion influx into the cell have been in part clarified, classifying them in “gating-defective” or “expression-defective” mutations. To date, the treatment of MC is only palliative because no direct ClC-1 activator is available. An ideal drug should be one which is able to correct biophysical defects of ClC-1 in the case of gating-defective mutations or a drug capable to recover ClC-1 protein expression on the plasma membrane for trafficking-defective ones. In this study, we tested the ability of niflumic acid (NFA), a commercial nonsteroidal anti-inflammatory drug, to act as a pharmacological chaperone on trafficking-defective MC mutants (A531V, V947E). Wild-type (WT) or MC mutant ClC-1 channels were expressed in HEK293 cells and whole-cell chloride currents were recorded with the patch-clamp technique before and after NFA incubation. Membrane biotinylation assays and western blot were performed to support electrophysiological results. A531V and V947E mutations caused a decrease in chloride current density due to a reduction of ClC-1 total protein level and channel expression on the plasma membrane. The treatment of A531V and V947E-transfected cells with 50 µM NFA restored chloride currents, reaching levels similar to those of WT. Furthermore, no significant difference was observed in voltage dependence, suggesting that NFA increased protein membrane expression without altering the function of ClC-1. Indeed, biochemical experiments confirmed that V947E total protein expression and its plasma membrane distribution were recovered after NFA incubation, reaching protein levels similar to WT. Thus, the use of NFA as a pharmacological chaperone in trafficking defective ClC-1 channel mutations could represent a good strategy in the treatment of MC. Because of the favorable safety profile of this drug, our study may easily open the way for confirmatory human pilot studies aimed at verifying the antimyotonic activity of NFA in selected patients carrying specific ClC-1 channel mutations.

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Section: Discussionmentioning

confidence: 99%

“…To date, at least 11 MC mutations are associated with ClC-1 proteostasis impairment ( Altamura et al, 2020b ; Jeng et al, 2020 ). This number is likely underestimated as targeted biochemical analyses are lacking for a number of other ClC-1 mutants ( Jeng et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Chaperone activity of niflumic acid on ClC-1 chloride channel mutants causing myotonia congenita

et al. 2022

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“…More than 250 CLCN1 mutations have been found to be associated with MC. They scattered over the entire sequence of the channel protein, but a few regions with high-frequency mutations have been described in exons 4, 5, and 8 [ 2 , 239 , 240 , 241 ]. With the exception of a few nonsense mutations leading to truncated ClC-1 proteins, all dominant mutations are missense mutations.…”

Section: Chloride Channel-related Muscle Disordersmentioning

confidence: 99%

“…The majority of MC mutations are predicted to reduce chloride currents by impaired ClC-1 proteostasis (impaired synthesis, defective cell trafficking, increased degradation) or by impairing ClC-1 function through various gating defects. The latter one includes a positive shift of the voltage-dependent activation of fast and slow channel gating, reduction of single-channel conductance, altered ion selectivity, or an inverted voltage dependence (hyperpolarization-activated) [ 241 , 244 , 245 , 246 , 247 , 248 , 249 ]. A number of ClC-1 mutations found in myotonic patients show no evidence of any functional defect when studied in heterologous expression systems.…”

Section: Chloride Channel-related Muscle Disordersmentioning

confidence: 99%

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Maggi

Bonanno

Altamura

et al. 2021

Cells

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Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments.

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“…Unfortunately, no direct activator of ClC-1 channel is known. Some studies aimed at deciphering the molecular interaction of known inhibitors with ClC-1 channels might provide some hints for the discovery of activators (gating modifiers) or pharmacological chaperones (trafficking correctors) [116][117][118][119]. Recently, two small molecules inhibiting ClC-1 ubiquitination showed in vitro effectiveness in correcting the impaired trafficking of misfolded ClC-1 protein [120,121].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

Desaphy

Altamura

Vicart

et al. 2021

JND

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Background: Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP. Objective: This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background. Methods: We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process. Results: For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from DCP compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies. Conclusions: These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.

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Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia

Cited by 6 publications

References 36 publications

Chaperone activity of niflumic acid on ClC-1 chloride channel mutants causing myotonia congenita

Chaperone activity of niflumic acid on ClC-1 chloride channel mutants causing myotonia congenita

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

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