Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice.

Gronemeier, Monika; Condie, Alison; Prosser, J.; Steinmeyer, Klaus; Jentsch, Tj; Jockusch, Harald

doi:10.1016/s0021-9258(17)37556-7

Cited by 64 publications

(5 citation statements)

References 31 publications

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“…1B). The used ADR mutant mouse truncates the ClC-1 protein at a clearly nonfunctional 46 amino acid, giving absolutely no ClC-1 expression in the ADR/ADR homozygote and a different phenotype compared with WT (15,17). Furthermore, other negative control samples, including rat kidney, heart, and brain tissue, did not reveal any signals at the migration around 120 kDa (Fig.…”

Section: Antibody Specificitymentioning

confidence: 93%

“…The ADR mouse strain was SWR/J-Clcn1 adr-mto /J (from The Jackson Laboratory JAX stock #000939). The specific alteration in this ADR mutant mouse is a nonsense mutation at codon 47 (C to T transition) that changes an arginine codon into a stop codon ahead of the first transmembrane region of CLCN1, truncating the protein at a clearly nonfunctional 46 amino acid (15). With this mutation, there should be no ClC-1 produced in the homozygote.…”

Section: Muscle Samplesmentioning

confidence: 99%

See 1 more Smart Citation

Abundance of ClC-1 chloride channel in human skeletal muscle: fiber type specific differences and effect of training

Thomassen

Hostrup

Murphy

et al. 2018

Journal of Applied Physiology

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Cl channel protein 1 (ClC-1) may be important for excitability and contractility in skeletal muscle, but ClC-1 abundance has not been examined in human muscle. The aim of the present study was to examine ClC-1 abundance in human skeletal muscle, including fiber type specific differences and the effect of exercise training. A commercially available antibody was tested with positive and negative control tissue, and it recognized specifically ClC-1 in the range from 100 to 150 kDa. Abundance of ClC-1 was 38% higher ( P < 0.01) in fast twitch Type IIa muscle fibers than in slow twitch Type I. Muscle ClC-1 abundance did not change with 4 wk of training consisting of 30 min cycling at 85% of maximal heart rate (HR) and 3 × 30-s all out sprints or during a 7-wk training period with 10-12 × 30 s uphill cycling and 4-5 × ~4 min cycling at 90%-95% of HR. ClC-1 abundance correlated negatively ( P < 0.01) with maximal oxygen consumption ( r = -0.552) and incremental exercise performance ( r = -0.546). In addition, trained cyclists had lower ( P < 0.01) ClC-1 abundance than lesser trained individuals. The present observations indicate that a low abundance of muscle ClC-1 may be beneficial for exercise performance, but the role of abundance and regulation of ClC-1 in skeletal muscle of humans with respect to exercise performance and trainability need to be elucidated. NEW & NOTEWORTHY Abundance of the Cl channel protein 1 (ClC-1) chloride channel may be important for excitability and contractility in human skeletal muscle and may therefore have implications for fatigue development. In this study, we confirmed ClC-1 specificity for a commercially available antibody, and this study is first to our knowledge to determine ClC-1 protein abundance in human muscle by Western blotting. We observed that abundance of ClC-1 was higher in fast compared with slow twitch fibers and lower in trained individuals than in recreationally active.

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Section: Antibody Specificitymentioning

confidence: 93%

Section: Muscle Samplesmentioning

confidence: 99%

Abundance of ClC-1 chloride channel in human skeletal muscle: fiber type specific differences and effect of training

Thomassen

Hostrup

Murphy

et al. 2018

Journal of Applied Physiology

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“…In humans, congenital myotonia, type Thomsen [14] and generalized myotonia, type Becker [15] are inherited as an autosomal dominant and recessive trait, respectively [3]. Mutations of the CLCN1 gene have been identified in adr/adr mice [8] and "fainting" goats [4]. Further, CLCN1 animal models have been described in dogs.…”

Section: Discussionmentioning

confidence: 99%

“…The association between myotonia and chloride conduction was first described in myotonic mice [8] and the first mutation in the CLCN1 gene shown to cause myotonia was found in domestic animals. The "fainting" goats which developed severe acute muscle stiffness and became immobile during vigorous movements or when startled showed a missense mutation of the CLCN1 gene (p.A885P) [4].…”

Section: Introductionmentioning

confidence: 99%

A missense mutation in the skeletal muscle chloride channel 1 (CLCN1) as candidate causal mutation for congenital myotonia in a New Forest pony

Wijnberg

Owczarek‐Lipska

Sacchetto

et al. 2012

Neuromuscular Disorders

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A 7-month-old New Forest foal presented for episodes of recumbency and stiffness with myotonic discharges on electromyography. The observed phenotype resembled congenital myotonia caused by CLCN1 mutations in goats and humans. Mutation of the CLCN1 gene was considered as possible cause and mutation analysis was performed. The affected foal was homozygous for a missense mutation (c.1775A>C, p.D592A) located in a well conserved domain of the CLCN1 gene. The mutation showed a recessive mode of inheritance within the reported pony family. Therefore, this CLCN1 polymorphism is considered to be a possible cause of congenital myotonia.

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“…6 In the case of myotonia research, the muscle-specific manifestation 7 and molecular basis 8 of this disorder has been clarified by the analysis of a myotonic mouse mutant, 9 the ADR mouse (phenotype ADR, genotype Clc1 adr/adr ). 10 Myotonia in the mouse is caused by insertional (allele adr 8 ), nonsense (allele mto 11 ) or missense (allele adr*K) 11 mutations at the gene locus Clc1 (chromosome 6) for the muscular chloride channel ClC-1. In human myotonia, a large number of both recessive (type Becker) and dominant (type Thomsen) mutations at the gene locus CLCN1 (chromosome 7) have been identified.…”

Section: Introductionmentioning

confidence: 99%

Identification of secondary effects of hyperexcitability by proteomic profiling of myotonic mouse muscle

et al. 2011

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Myotonia is a symptom of various genetic and acquired skeletal muscular disorders and is characterized by hyperexcitability of the sarcolemma. Here, we have performed a comparative proteomic study of the genetic mouse models ADR, MTO and MTO*5J of human congenital myotonia in order to determine myotonia-specific changes in the global protein complement of gastrocnemius muscle. Proteomic analyses of myotonia in the mouse, which is caused by mutations in the gene encoding the muscular chloride channel Clc1, revealed a generally perturbed protein expression pattern in severely affected ADR and MTO muscle, but less pronounced alterations in mildly diseased MTO*5J mice. Alterations were found in major metabolic pathways, the contractile machinery, ion handling elements, the cellular stress response and cell signaling mechanisms, clearly confirming a glycolytic-to-oxidative transformation process in myotonic fast muscle. In the long-term, a detailed biomarker signature of myotonia will improve our understanding of the pathobiochemical processes underlying this disorder and be helpful in determining how a single mutation in a tissue-specific gene can trigger severe downstream effects on the expression levels of a very large number of genes in contractile tissues.

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Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice.

Cited by 64 publications

References 31 publications

Abundance of ClC-1 chloride channel in human skeletal muscle: fiber type specific differences and effect of training

Abundance of ClC-1 chloride channel in human skeletal muscle: fiber type specific differences and effect of training

A missense mutation in the skeletal muscle chloride channel 1 (CLCN1) as candidate causal mutation for congenital myotonia in a New Forest pony

Identification of secondary effects of hyperexcitability by proteomic profiling of myotonic mouse muscle

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