Document Detail

Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions.
MedLine Citation:
PMID:  17932099     Owner:  NLM     Status:  MEDLINE    
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.
D Fialho; S Schorge; U Pucovska; N P Davies; R Labrum; A Haworth; E Stanley; R Sud; W Wakeling; M B Davis; D M Kullmann; M G Hanna
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-10-11
Journal Detail:
Title:  Brain : a journal of neurology     Volume:  130     ISSN:  1460-2156     ISO Abbreviation:  Brain     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-06     Completed Date:  2008-02-05     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  0372537     Medline TA:  Brain     Country:  England    
Other Details:
Languages:  eng     Pagination:  3265-74     Citation Subset:  AIM; IM    
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MeSH Terms
Chloride Channels / genetics*
Cohort Studies
DNA Mutational Analysis / methods
Exons / genetics
Genes, Dominant
Genetic Testing / methods
Mutagenesis, Site-Directed
Myotonia Congenita / diagnosis,  genetics*
Polymorphism, Restriction Fragment Length
Grant Support
1 U54 RR198442-01/RR/NCRR NIH HHS; G0200373//Medical Research Council; G0601440//Medical Research Council; //Wellcome Trust
Reg. No./Substance:
0/CLC-1 channel; 0/Chloride Channels

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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