Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia

European Journal of Human Genetics volume 9, pages 903–909 (2001)Cite this article

A Corrigendum to this article was published on 14 January 2010

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.

Download PDF

References

  1. Rüdel R, Lehmann-Horn F . Membrane changes in cells from myotonia patients Physiol Rev 1985 65: 310–356

    Article  Google Scholar 

  2. Rüdel R, Ricker K, Lehmann-Horn F . Transient weakness and altered membrane characteristic in recessive generalized myotonia (Becker) Muscle Nerve 1988 11: 202–211

    Article  Google Scholar 

  3. Franke C, Iaizzo PA, Hatt H, Spittelmeister W, Ricker K, Lehmann-Horn F . Altered Na+ channel activity and reduced Cl− conductance cause hyperexcitability in recessive generalised myotonia (Becker) Muscle Nerve 1991 14: 762–770

    CAS  Article  Google Scholar 

  4. Koch MC, Steinmeyer K, Lorenz C et al. The skeletal muscle chloride channel in dominant and recessive human myotonia Science 1992 257: 797–800

    CAS  Article  Google Scholar 

  5. Lorenz C, Meyer-Kleine C, Steinmeyer K, Koch MC, Jentsch TJ . Genomic organization of the human muscle chloride channel ClC-1 and analysis of novel mutations leading to Becker-type myotonia Hum Mol Genet 1994 3: 841–846

    Article  Google Scholar 

  6. Mailänder V, Heine R, Deymeer F, Lehmann-Horn F . Novel muscle chloride channel mutations and their effects on heterozygous carriers Am J Hum Genet 1996 58: 317–324

    PubMed  PubMed Central  Google Scholar 

  7. Kubisch C, Schmidt-Rose T, Fontaine B, Bretag AH, Jentsch TJ . ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence Hum Mol Genet 1998 7: 1753–1760

    CAS  Article  Google Scholar 

  8. Meyer-Kleine C, Steinmeyer K, Ricker K, Jentsh TJ, Koch MC . Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia Am J Hum Genet 1995 57: 1325–1334

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Papponen H, Toppinen T, Baumann P et al. Founder mutations and the high prevalence of myotonia congenita in a Northern Finland Neurology 1999 53: 297–302

    CAS  Article  Google Scholar 

  10. Emery AE . Population frequencies of inherited neuromuscular diseases – a world survey Neuromusc Disord 1991 1: 19–29

    CAS  Article  Google Scholar 

  11. Baumann P, Myllylä VV, Leisti J . Myotonia congenita in northern Finland: an epidemiological and genetic study J Med Genet 1998 35: 293–296

    CAS  Article  Google Scholar 

  12. Sloan-Brown K, George Jr AL . Inheritance of three distinct muscle chloride channel gene (CLCN1) mutations in a single recessive myotonia congenita family Neuorology 1997 48: 542–543

    CAS  Article  Google Scholar 

  13. George Jr AL, Sloan-Brown K, Fenichel GM, Mitchell GA, Spiegel R, Pascuzzi RM . Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita Hum Mol Genet 1994 3: 2071–2072

    CAS  Google Scholar 

  14. Koty PP, Pegoraro E, Hobson G et al. Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect Neurology 1996 47: 963–968

    CAS  Article  Google Scholar 

  15. Sangiuolo F, Botta A, Mesoraca A et al. Identification of five new mutations and three novel polymorphisms in the muscle chloride channel gene (CLCN1) in 20 Italian patients with dominant and recessive myotonia congenita Hum Mut 1998 11: 331–334

  16. Mastaglia FL, Harker N, Phillips BA et al. Dominantly inherited proximal myotonic myopathy and leukoencephalopathy in a family with an incidental CLCN1 mutation J Neurol Neurosurg Psychiatry 1998 64: 543–547

    CAS  Article  Google Scholar 

  17. Sun C, Henriksen OA, Tranebjærg L . Proximal myotonic myopathy: clinical and molecular investigation of a Norwegian family with PROMM Clin Genet 1999 56: 457–461

    CAS  Article  Google Scholar 

  18. Plassart-Schiess E, Gervais A, Eymard B et al. Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance Neurology 1998 50: 1176–1179

    CAS  Article  Google Scholar 

Download references

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.

Author information

Affiliations

  1. Department of Medical Genetics, University Hospital of Tromsø, Tromsø, Norway

    Chen Sun, Lisbeth Tranebjærg & Marijke Van Ghelue

  2. Department of Neurology, University Hospital of Tromsø, Tromsø, Norway

    Torberg Torbergsen

  3. Department of Clinical Genetics, University Hospital of Umeå, Umeå, Sweden

    Gösta Holmgren

  4. Department of Biochemistry, Section Molecular Biology, University of Tromsø, Tromsø, Norway

    Marijke Van Ghelue

Authors
  1. Chen Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisbeth Tranebjærg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Torberg Torbergsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gösta Holmgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marijke Van Ghelue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lisbeth Tranebjærg.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ejhg.5200736

Keywords

  • myotonia
  • myotonia congenita
  • prevalence
  • CLCN1
  • population frequencies
  • genetic heterogeneity

Further reading

Search

Advanced search

Quick links