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Mutational spectrum in the Ca2+-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances

Authors

  • Birgit Stallmeyer,

    Corresponding author
    1. Institut für Genetik von Herzerkrankungen (IfGH), Universitätsklinikum Münster, Münster, Germany
    2. Interdisziplinäres Zentrum für klinische Forschung (IZKF), Universität Münster, Münster, Germany
    • Institut für Genetik von Herzerkrankungen (IfGH), Universitätsklinikum Münster (UKM), Domagkstr. 3, D-48149 Münster, Germany
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    • Both authors contributed equally to this paper.

  • Sven Zumhagen,

    1. Institut für Genetik von Herzerkrankungen (IfGH), Universitätsklinikum Münster, Münster, Germany
    2. Department für Kardiologie und Angiologie, Universitätsklinikum Münster, Münster, Germany
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    • Both authors contributed equally to this paper.

  • Isabelle Denjoy,

    1. Inserm, U956, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    2. AP-HP, Service de Cardiologie, Hôpital Lariboisière, Centre de Référence Maladies Cardiaques Héréditaires, Paris, France
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  • Guillaume Duthoit,

    1. Inserm, U956, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    2. AP-HP, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Jean-Louis Hébert,

    1. AP-HP, Laboratoire d'Explorations Fonctionnelles Cardiorespiratoires, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
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  • Xavier Ferrer,

    1. Centre de Référence des Maladies Neuromusculaires, CHU de Bordeaux, France
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  • Svetlana Maugenre,

    1. Inserm, U956, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    2. UPMC Univ. Paris 06, UMR_S956, IFR14, Paris, France
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  • Wilhelm Schmitz,

    1. Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Münster, Germany
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  • Uwe Kirchhefer,

    1. Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Münster, Germany
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  • Ellen Schulze-Bahr,

    1. Institut für Genetik von Herzerkrankungen (IfGH), Universitätsklinikum Münster, Münster, Germany
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  • Pascale Guicheney,

    1. Inserm, U956, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    2. UPMC Univ. Paris 06, UMR_S956, IFR14, Paris, France
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  • Eric Schulze-Bahr

    1. Institut für Genetik von Herzerkrankungen (IfGH), Universitätsklinikum Münster, Münster, Germany
    2. Interdisziplinäres Zentrum für klinische Forschung (IZKF), Universität Münster, Münster, Germany
    3. Department für Kardiologie und Angiologie, Universitätsklinikum Münster, Münster, Germany
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  • Communicated by Nancy B. Spinner

Abstract

Very recently, mutations in the TRPM4 gene have been identified in four pedigrees as the cause of an autosomal dominant form of cardiac conduction disease. To determine the role of TRPM4 gene variations, the relative frequency of TRPM4 mutations and associated phenotypes was assessed in a cohort of 160 unrelated patients with various types of inherited cardiac arrhythmic syndro-mes. In eight probands with atrioventricular block or right bundle branch block—five familial cases and three spora-dic cases—a total of six novel and two published TRPM4 mutations were identified. In patients with sinus node dysfunction, Brugada syndrome, or long-QT syndrome, no mutations were found. The novel mutations include six amino acid substitutions and appeared randomly distributed through predicted TRPM4 protein. In addition, eight polymorphic sites including two in-frame deletions were found. Mutations separated from polymorphisms by absence in control individuals and familial cosegregation in some families. In summary, TRPM4 gene mutations appear to play a major role in cardiac conduction disease but not for other related syndromes so far. The phenotypes are variable and clearly suggestive of additional factors modulating the disease phenotype in some patients. Hum Mutat 33:109–117, 2012. © 2011 Wiley Periodicals, Inc.

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