Abstract
Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.
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Acknowledgements
We would like to acknowledge the financial support from ‘The Norwegian Research Council (NFR)’ to Chen Sun (project no. 12366/310) and from the ‘Association for Patients with Muscular Disorders (Foreningen for Muskelsyke, FFM)’ to Lisbeth Tranebjærg. We would also thank Markus Perola (First Department of Medicine, Helsinki University Central Hospital, Finland) for providing the Finnish control DNA samples, prof. Christoph Falhke (Department of Physiology, University Hospital of Aachen, Germany) for the cDNA, and prof. Eric Hoffman (Research Center for Genetic Medicine, Children's National Medical Center, Washington DC, USA) for stimulating discussions.
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Sun, C., Tranebjærg, L., Torbergsen, T. et al. Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. Eur J Hum Genet 9, 903–909 (2001). https://doi.org/10.1038/sj.ejhg.5200736
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DOI: https://doi.org/10.1038/sj.ejhg.5200736
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