Myotonia caused by mutations in the muscle chloride channel geneCLCN1

Pusch, Michael

doi:10.1002/humu.10063

Cited by 203 publications

(192 citation statements)

References 66 publications

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“…14 However, the same mutation has subsequently been found the recessive families. 3 It is quite possible that allelic variation in favor for the mutation is recognized as a dominant phenotype, whereas a shift to the wild-type allele leads to recessive inheritance. Thus, expression of the normal allele below a critical threshold could result in altered disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…3 -5 The vast majority of these are found in recessive pedigrees, whereas approximately only 10 mutations exclusively result in dominant MC presumably through a dominant-negative effect. 6 More that 10 mutations have been associated with both recessive and dominant MC, 3 making a clear distinction between the two modes of inheritance of the disease difficult. This peculiar phenomenon has been explained by reduced penetrance of dominant-negative mutations, incomplete dominance, founder effect and incomplete mutation detection.…”

Section: Introductionmentioning

confidence: 99%

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Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

et al. 2004

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Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker's myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen's myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

et al. 2004

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“…Common gating of ClC-1 channels is medically important because the vast proportion of ClC-1 mutations that cause myotonia congenita affect the voltage dependence of the common gate 21 . Common gating involves widespread 22,23 cooperative conformational rearrangements that appear to be communicated across the intersubunit interface 24 .…”

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confidence: 99%

Molecular determinants of common gating of a ClC chloride channel

Bennetts

Parker

2013

Nat Commun

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Uniquely, the ClC family harbours dissipative channels and anion/H þ transporters that share unprecedented functional characteristics. ClC-1 channels are homodimers in which each monomer supports an identical pore carrying three anion-binding sites. Transient occupancy of the extracellular binding site by a conserved glutamate residue, E232, independently gates each pore. A common gate, the molecular basis of which is unknown, closes both pores simultaneously. Mutations affecting common gating underlie myotonia congenita in humans. Here we show that the common gate likely occludes the channel pore via interaction of E232 with a highly conserved tyrosine, Y578, at the central anion-binding site. We also identify structural linkages important for coordination of common gating between subunits and modulation by intracellular molecules. Our data reveal important molecular determinants of common gating of ClC channels and suggest that the molecular mechanism is an evolutionary vestige of coupled anion/H þ transport.

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“…The importance of this function of ClC-1 is underscored by the genetic disease myotonia, in which loss-of-function mutations of ClC-1 lead to skeletal muscle hyper-excitability (6). Many myotonia-causing mutations shift ClC-1 voltage dependence to more positive potentials resulting in channel inhibition across the physiological voltage range (7).…”

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confidence: 99%

Inhibition of Skeletal Muscle ClC-1 Chloride Channels by Low Intracellular pH and ATP

Bennetts

Parker²,

Cromer

2007

Journal of Biological Chemistry

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Skeletal muscle acidosis during exercise has long been thought to be a cause of fatigue, but recent studies have shown that acidosis maintains muscle excitability and opposes fatigue by decreasing the sarcolemmal chloride conductance. ClC-1 is the primary sarcolemmal chloride channel and has a clear role in controlling muscle excitability, but recombinant ClC-1 has been reported to be activated by acidosis. Following our recent finding that intracellular ATP inhibits ClC-1, we investigated here the interaction between pH and ATP regulation of ClC-1. We found that, in the absence of ATP, intracellular acidosis from pH 7.2 to 6.2 inhibited ClC-1 slightly by shifting the voltage dependence of common gating to more positive potentials, similar to the effect of ATP. Importantly, the effects of ATP and acidosis were cooperative, such that ATP greatly potentiated the effect of acidosis. Adenosine had a similar effect to ATP at pH 7.2, but acidosis did not potentiate this effect, indicating that the phosphates of ATP are important for this cooperativity, possibly due to electrostatic interactions with protonatable residues of ClC-1. A protonatable residue identified by molecular modeling, His-847, was found to be critical for both pH and ATP modulation and may be involved in such electrostatic interactions. These findings are now consistent with, and provide a molecular explanation for, acidosis opposing fatigue by decreasing the chloride conductance of skeletal muscle via inhibition of ClC-1. The modulation of ClC-1 by ATP is a key component of this molecular mechanism.

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Myotonia caused by mutations in the muscle chloride channel geneCLCN1

Cited by 203 publications

References 66 publications

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

Molecular determinants of common gating of a ClC chloride channel

Inhibition of Skeletal Muscle ClC-1 Chloride Channels by Low Intracellular pH and ATP

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