The spectrum of CLCN1 gene mutations in patients with nondystrophic Thomsen’s and Becker’s myotonias

Иванова, Е. А.; Дадали, Е. Л.; Федотов, В. П.; Kurbatov, S. V.; Rudenskaya, G. E.; Проскокова, Т Н; Polyakov, A. V.

doi:10.1134/s1022795412090049

Cited by 10 publications

(9 citation statements)

References 18 publications

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“…In particular, all three mutations are the most frequently detected mutations in United Kingdom [ 39 ]. The mutation p.(Arg894*) is the most frequently observed mutation in Russia [ 47 ], Northern Scandinavia [ 48 ], and Denmark [ 32 ], but it is also significantly represented in Netherlands [ 49 ], Spain [ 40 ] and Italy [ 50 ]. The p.(Phe413Cys) belongs to one of the three most frequent mutations in Northern Scandinavia and Netherlands and the c.1437_1450del mutation to one of the three most frequent mutations in Russia and Denmark.…”

Section: Discussionmentioning

confidence: 99%

CLCN1 Mutations in Czech Patients with Myotonia Congenita, In Silico Analysis of Novel and Known Mutations in the Human Dimeric Skeletal Muscle Chloride Channel

et al. 2013

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Myotonia congenita (MC) is a genetic disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1) encoding the skeletal muscle chloride channel (ClC-1). Mutations of CLCN1 result in either autosomal dominant MC (Thomsen disease) or autosomal recessive MC (Becker disease). The ClC-1 protein is a homodimer with a separate ion pore within each monomer. Mutations causing recessive myotonia most likely affect properties of only the mutant monomer in the heterodimer, leaving the wild type monomer unaffected, while mutations causing dominant myotonia affect properties of both subunits in the heterodimer. Our study addresses two points: 1) molecular genetic diagnostics of MC by analysis of the CLCN1 gene and 2) structural analysis of mutations in the homology model of the human dimeric ClC-1 protein. In the first part, 34 different types of CLCN1 mutations were identified in 51 MC probands (14 mutations were new). In the second part, on the basis of the homology model we identified the amino acids which forming the dimer interface and those which form the Cl- ion pathway. In the literature, we searched for mutations of these amino acids for which functional analyses were performed to assess the correlation between localisation of a mutation and occurrence of a dominant-negative effect (corresponding to dominant MC). This revealed that both types of mutations, with and without a dominant-negative effect, are localised at the dimer interface while solely mutations without a dominant-negative effect occur inside the chloride channel. This work is complemented by structural analysis of the homology model which provides elucidation of the effects of mutations, including a description of impacts of newly detected missense mutations.

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Section: Discussionmentioning

confidence: 99%

CLCN1 Mutations in Czech Patients with Myotonia Congenita, In Silico Analysis of Novel and Known Mutations in the Human Dimeric Skeletal Muscle Chloride Channel

et al. 2013

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“…Misfolded proteins reaching the plasma membrane may also be removed by the peripheral quality control system and degraded through the endosome/lysosome pathway. Such mechanisms are also valid for misfolded ClC-1 mutants causing myotonia congenita ( 7 ). In the case of G411C, we observed that the total protein expression level was similar to WT, suggesting that there was no enhancement of protein degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA was extracted from peripheral blood cells according to the standard method with DLAtom™ DNA Prep100 kit. All the 23 exons of CLCN1 were amplified by polymerase chain reaction (PCR) and were sequenced using intronic primers, as previously described ( 7 ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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Objective: Myotonia congenita (MC) is a rare muscle disease characterized by sarcolemma over-excitability inducing skeletal muscle stiffness. It can be inherited either as an autosomal dominant (Thomsen's disease) or an autosomal recessive (Becker's disease) trait. Both types are caused by loss-of-function mutations in the CLCN1 gene, encoding for ClC-1 chloride channel. We found a ClC-1 mutation, p.G411C, identified in Russian patients who suffered from a severe form of Becker's disease. The purpose of this study was to provide a solid correlation between G411C dysfunction and clinical symptoms in the affected patient. Methods: We provide clinical and genetic information of the proband kindred. Functional studies include patch-clamp electrophysiology, biotinylation assay, western blot analysis, and confocal imaging of G411C and wild-type ClC-1 channels expressed in HEK293T cells. Results: The G411C mutation dramatically abolished chloride currents in transfected HEK cells. Biochemical experiments revealed that the majority of G411C mutant channels did not reach the plasma membrane but remained trapped in the cytoplasm. Treatment with the proteasome inhibitor MG132 reduced the degradation rate of G411C mutant channels, leading to their expression at the plasma membrane. However, despite an increase in cell surface expression, no significant chloride current was recorded in the G411C-transfected cell treated with MG132, suggesting that this mutation produces non-functional ClC-1 chloride channels. Conclusion: These results suggest that the molecular pathophysiology of G411C is linked to a reduced plasma membrane expression and biophysical dysfunction of mutant channels, likely due to a misfolding defect. Chloride current abolition confirms that the mutation is responsible for the clinical phenotype.

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“…9 Moreover, one mutation (IVS19 C 2T > A) at the same location in CLCN1 gene implied probable disease-causing reason as recessive alleles in Italian and Russian patients. 21,22 Thus we speculated that combined effect of both mutations may have a prominent impact on the functioning of CLC-1, thus resulting in the typical clinical symptoms of myotonia. However, the exact mechanism underlying the occurrence of myotonia needs to be investigated future.…”

Section: Discussionmentioning

confidence: 99%

Myotonia congenita: novel mutations in CLCN1 gene

et al. 2015

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The spectrum of CLCN1 gene mutations in patients with nondystrophic Thomsen’s and Becker’s myotonias

Cited by 10 publications

References 18 publications

CLCN1 Mutations in Czech Patients with Myotonia Congenita, In Silico Analysis of Novel and Known Mutations in the Human Dimeric Skeletal Muscle Chloride Channel

CLCN1 Mutations in Czech Patients with Myotonia Congenita, In Silico Analysis of Novel and Known Mutations in the Human Dimeric Skeletal Muscle Chloride Channel

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

Myotonia congenita: novel mutations in CLCN1 gene

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