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Myotonia congenita and myotonic dystrophy in the same family: coexistence of a CLCN1 mutation and expansion in the CNBP (ZNF9) gene

Authors

  • C Sun,

    Corresponding author
    1. Department of Clinical Medicine – Medical Genetics, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
    2. Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
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  • M Van Ghelue,

    1. Department of Clinical Medicine – Medical Genetics, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
    2. Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway
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  • L Tranebjærg,

    1. Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway
    2. Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark
    3. Wilhelm Johannsen Centre of Functional Genomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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  • F Thyssen,

    1. Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway
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  • Ø Nilssen,

    1. Department of Clinical Medicine – Medical Genetics, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
    2. Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway
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  • T Torbergsen

    1. Department of Neurology, University Hospital of North Norway, Tromsø, Norway
    2. Department of Neurology, National University Hospital, Oslo, Norway
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Chen Sun, MD, Department of Obstetrics and Gynecology, Haukeland University Hospital, N-5021 Bergen, Norway.
Tel.: +47 5597 4200;
fax: +47 5597 4968;
e-mail: chen.sun@helse-bergen.no

Abstract

Sun C, Van Ghelue M, Tranebjærg L, Thyssen F, Nilssen Ø, Torbergsen T. Myotonia congenita and myotonic dystrophy in the same family: coexistence of a CLCN1 mutation and expansion in the CNBP (ZNF9) gene.

Myotonia is characterized by hyperexcitability of the muscle cell membrane. Myotonic disorders are divided into two main categories: non-dystrophic and dystrophic myotonias. The non-dystrophic myotonias involve solely the muscle system, whereas the dystrophic myotonias are characterized by multisystem involvement and additional muscle weakness. Each category is further subdivided into different groups according to additional clinical features or/and underlying genetic defects. However, the phenotypes and the pathological mechanisms of these myotonic disorders are still not entirely understood. Currently, four genes are identified to be involved in myotonia: the muscle voltage-gated sodium and chloride channel genes SCN4A and CLCN1, the myotonic dystrophy protein kinase (DMPK) gene, and the CCHC-type zinc finger, nucleic acid binding protein gene CNBP. Additional gene(s) and/or modifying factor(s) remain to be identified. In this study, we investigated a large Norwegian family with clinically different presentations of myotonic disorders. Molecular analysis revealed CCTG repeat expansions in the CNBP gene in all affected members, confirming that they have myotonic dystrophy type 2. However, a CLCN1 mutation c.1238C>G, causing p.Phe413Cys, was also identified in several affected family members. Heterozygosity for p.Phe413Cys seems to exaggerate the severity of myotonia and thereby, to some degree, contributing to the pronounced variability in the myotonic phenotype in this family.

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