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: 4.6).
07/2013; 6(4). DOI: 10.1161/CIRCGENETICS.113.000097
-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.
Available from: Kathryn J Swoboda
- "The North American Hutterites are one of the bestcharacterized young founder populations (Boycott et al. 2008; Hostetler 1974; Ober et al. 2001; Steinberg et al. 1967), with more than 36 autosomal recessive (AR) diseases reported in members of this population (Beaulieu et al. 2013; Bogershausen et al. 2013; Boycott et al. 2008, 2010; Caliskan et al. 2011; Gerull et al. 2013; Huang et al. 2011; Wiltshire et al. 2013), such as Joubert syndrome, restrictive dermopathy, and nonsyndromic deafness. The Hutterites are an Anabaptist religious group that originated during the 1500s in the Tyrolean Alps. "
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ABSTRACT: There is currently extensive discussion and debate in the literature on how, when, and to whom genetic research results should be returned (see Genetics in Medicine, April 2012 issue). Here, we describe our experience in disclosing genetic information on Mendelian disorders discovered during the course of our research in the Hutterites. We first assessed attitudes toward the disclosure of carrier results, which revealed that many individuals wanted carrier information and that many intended to use the information in family planning. Based on this information, we developed a pilot study to test and disclose cystic fibrosis (CF) carrier status. Next, a larger scale project was developed in order to disclose genetic research results for 14 diseases to those interested in receiving the information. We developed brochures, offered a live interactive educational program, conducted a consent process, and disclosed results in letters mailed to the consented individuals. Overall, ~80 % of individuals who participated in the educational program signed consent forms for the release of their results for 14 diseases. We describe our experience with returning individual genetic research results to participants in a population-based research study.
Available from: Andreas Brodehl
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ABSTRACT: -The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known.
-We identified the two novel variants DES-p.A120D (c.359C>A) and p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D evidenced a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein, respectively. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type.
-Due to the functional in vivo and in vitro characterization DES-p.A120D has to be regarded as a pathogenic mutation, whereas DES-p.H326R is a rare variant with unknown significance, respectively. Presumably, the loss of the desmin-p.A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.
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ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential.
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