Homozygous Founder Mutation in Desmocollin-2 ( <i>DSC2</i> ) Causes Arrhythmogenic Cardiomyopathy in the Hutterite Population

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  • Brenda Gerull
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Florian Kirchner
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Jessica X. Chong
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Julia Tagoe
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Kumaran Chandrasekharan
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Oliver Strohm
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Darrel Waggoner
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Carole Ober
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).
  • Henry J. Duff
    From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (B.G., K.C., O.S., H.J.D.), and Department of Medical Genetics (B.G., J.T.), University of Calgary, Calgary, AB, Canada; Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.K.); Department of Human Genetics, The University of Chicago, Chicago, IL (J.X.C., D.W., C.O.); and Centre for Cardiology, Baden-Baden, Germany (O.S.).

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<jats:sec> <jats:title>Background—</jats:title> <jats:p>Dominant mutations in cellular junction proteins are the major cause of arrhythmogenic cardiomyopathy, whereas recessive mutations in those proteins cause cardiocutaneous syndromes such as Naxos and Carvajal syndrome. The Hutterites are distinct genetic isolates who settled in North America in 1874. Descended from <100 founders, they trace their origins to 16th-century Europe.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> We clinically and genetically evaluated 2 large families of the Alberta Hutterite population with a history of sudden death and found several individuals with severe forms of biventricular cardiomyopathy characterized by mainly left-sided localized aneurysms, regions of wall thinning with segmental akinesis, in addition to typical electric and histological features known for arrhythmogenic right ventricular cardiomyopathy. We identified a homozygous truncation mutation, c.1660C>T (p.Q554X) in desmocollin-2 ( <jats:italic>DSC2</jats:italic> ), in affected individuals and determined a carrier frequency of this mutation of 9.4% (1 in 10.6) among 1535 Schmiedeleut Hutterites, suggesting a common founder in that subgroup. Immunohistochemistry of endomyocardial biopsy samples revealed altered expression of the truncated DSC2 protein at the intercalated discs but only minor changes in immunoreactivity of other desmosomal proteins. Recombinant expressed mutant DSC2 protein in cells confirmed a stable, partially processed truncated protein with cytoplasmic and membrane localization. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> A homozygous truncation mutation in <jats:italic>DSC2</jats:italic> leads to a cardiac-restricted phenotype of an early onset biventricular arrhythmogenic cardiomyopathy. The truncated protein remains partially stable and localized at the intercalated discs. These data suggest that the processed DSC2 protein plays a role in maintaining desmosome integrity and function. </jats:p> </jats:sec>

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