Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myotonia, defined as delayed relaxation of muscle after contraction, is seen in a group of genetic disorders that includes autosomal dominant myotonia congenita (Thomsen's disease) and autosomal recessive myotonia congenita (Becker's disease). Both disorders are characterized electrophysiologically by increased excitability of muscle fibers, reflected in clinical myotonia. These diseases are similar except that transient weakness is seen in patients with Becker's, but not Thomsen's disease. Becker's and Thomsen's diseases are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). Genetic screening of a panel of 18 consecutive myotonia congenita (MC) probands for mutation in CLCN1 revealed that a novel Gln-68-Stop nonsense mutation predicts premature truncation of the chloride channel protein. Four previously reported mutations, Arg-894-stop, Arg-338-Gln, Gly-230-Glu, and del 1437-1450, were also noted in our sample set. The Arg-338-Gln and Gly-230-Glu mutations were found in patients with different phenotypes from those of previous reports. Further study of the Arg-338-Gln and Gln-230-Glu alleles may shed light on variable modes of transmission (dominant versus recessive) in different families. Physiologic study of these mutations may lead to better understanding of the pathophysiology of myotonia in these patients and of voltage-gated chloride channel structure/function relationships in skeletal muscles.
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PMID:Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. 885 33

We investigated the skeletal muscle voltage-gated chloride channel gene (CLCN1) in two unrelated Japanese patients with Becker's myotonia congenita. The non-myotonic parents of each patient were consanguineous. The proband of each family shares generalized myotonia, transient weakness after rest, and leg muscle hypertrophy. However, the disease severity related to the degree of myotonia differed, even in view of the response to long train nerve stimulation tests. CLCN1 gene analysis revealed a novel Ala659Val missense mutation identified to be homozygous in the more severe patient, while a novel Gln445Stop nonsense mutation was present in the other patient. Both mutations were absent in 90 Japanese normal controls. This is the first report of Japanese cases of Becker's myotonia congenita with CLCN1 gene mutations.
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PMID:Novel chloride channel gene mutations in two unrelated Japanese families with Becker's autosomal recessive generalized myotonia. 1061 17

Acetazolamide, a carbonic anhydrase inhibitor, is used empirically in neuromuscular diseases with episodic ataxia, weakness, and myotonia, although not all of the mechanisms responsible for its therapeutic effects are understood. To elucidate whether acetazolamide acts directly on the human skeletal muscle voltage-gated chloride channel (ClC-1), which is associated with myotonia, we evaluated the effects of acetazolamide on ClC-1 expressed in cultured mammalian cells, using whole-cell recording. Acetazolamide significantly shifted the voltage dependency of the open probability (P(o)) toward negative potentials in a dose-dependent manner, resulting in an increase of chloride conductance at voltages near the resting membrane potential. This effect was attenuated when using a pipette solution containing 30 mmol/L Hepes. These results suggest that acetazolamide can influence the voltage-dependent opening gate of ClC-1 through a mechanism related to intracellular acidification by inhibiting carbonic anhydrase, and that the therapeutic effects of acetazolamide in neuromuscular diseases may be mediated by activation of ClC-1.
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PMID:Acetazolamide acts directly on the human skeletal muscle chloride channel. 1681 Jun 86

Myotonia congenita (MC) is the commonest genetic skeletal muscle ion channelopathy. It is caused by mutations in CLCN1 on chromosome 7q35, which alter the function of the major skeletal muscle voltage-gated chloride channel. Dominant and recessive forms of the disease exist. We have undertaken a clinical, genetic and molecular expression study based upon a large cohort of over 300 UK patients. In an initial cohort of 22 families, we sequenced the DNA of the entire coding region of CLCN1 and identified 11 novel and 11 known mutations allowing us to undertake a detailed genotype-phenotype correlation study. Generalized muscle hypertrophy, transient weakness and depressed tendon reflexes occurred more frequently in recessive than dominant MC. Mild cold exacerbation and significant muscle pain were equally common features in dominant and recessive cases. Dominant MC occurred in eight families. We noted that four newly identified dominant mutations clustered in exon 8, which codes for a highly conserved region of predicted interaction between the CLC-1 monomers. Expressed in Xenopus oocytes these mutations showed clear evidence of a dominant-negative effect. Based upon the analysis of mutations in this initial cohort as well as a review of published CLCN1 mutations, we devised an exon hierarchy analysis strategy for genetic screening. We applied this strategy to a second cohort of 303 UK cases with a suspected diagnosis of MC. In 23 individuals, we found two mutations and in 86 individuals we identified a single mutation. Interestingly, 40 of the cases with a single mutation had dominant exon 8 mutations. In total 48 individuals (from 34 families) in cohort 1 and 2 were found to harbour dominant mutations (37% of mutation positive individuals, 30% of mutation positive families). In total, we have identified 23 new disease causing mutations in MC, confirming the high degree of genetic heterogeneity associated with this disease. The DNA-based strategy we have devised achieved a genetic diagnosis in 36% of individuals referred to our centre. Based on these results, we propose that exon 8 of CLCN1 is a hot-spot for dominant mutations. Our molecular expression studies of the new exon 8 mutations indicate that this region of the chloride channel has an important role in dominant negative interactions between the two chloride channel monomers. Accurate genetic counselling in MC should be based not only upon clinical features and the inheritance pattern but also on molecular genetic analysis and ideally functional expression data.
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PMID:Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions. 1793 99

Multiple mutations in the CLCN1 gene coding for the voltage-gated chloride channel have been documented to cause myotonia congenita. We report a kindred featuring an index patient who possesses 2 copies of a dominantly inherited mutated CLCN1 allele with a resulting novel phenotypic presentation. The index patient is a boy who presented initially for evaluation at the age of 5 years with a 2-year history of gait problems. Both parents and 3 male siblings were entirely well. Examination revealed a striking diffuse muscular hypertrophy, diffuse mild to moderate weakness, Gower sign, percussion, and grip myotonia. Electromyography confirmed myotonia, and molecular analysis revealed 2 copies of the T310M mutation on the CLCN1 gene. Testing of family members revealed a normal neurological examination without clinical myotonia in all and electromyographic evidence of myotonia and a single copy of the T310M mutation in both parents and 2 siblings. Our kindred is the initial demonstration of the dosage effect of a dominant mutated allele in the CLCN1 gene.
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PMID:Dosage effect of a dominant CLCN1 mutation: a novel syndrome. 1826 54

The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl(-) homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases.
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PMID:ClC-1 chloride channels: state-of-the-art research and future challenges. 2596 41