A Homozygous Founder Mutation in Desmocollin-2 (DSC2) Causes Arrhythmogenic Cardiomyopathy in the Hutterite Population.

1Libin Cardiovascular Institute of Alberta & Departments of Cardiac Sciences and Medical Genetics, University of Calgary, Calgary, Canada.
Circulation Cardiovascular Genetics (Impact Factor: 5.34). 07/2013; DOI: 10.1161/CIRCGENETICS.113.000097
Source: PubMed

ABSTRACT -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 fewer than 100 founders, they trace their origins to the 16(th) century Europe.
-We clinically and genetically evaluated two 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 electrical and histological features known for arrhythmogenic right ventricular cardiomyopathy (ARVC). We identified a homozygous truncation mutation, c.1660C>T (p.Q554X) in desmocollin-2 (DSC2) in affected individuals, and determined a carrier frequency of this mutation of 9.4% (1 in 10.6) among 1,535 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.
-A homozygous truncation mutation in DSC2 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.