A Homozygous Founder Mutation in Desmocollin-2 (DSC2) Causes Arrhythmogenic Cardiomyopathy in the Hutterite Population.
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.
Article: Almanac 2014: cardiomyopathies.[Show abstract] [Hide abstract]
ABSTRACT: Cardiomyopathies are myocardial disorders that are not explained by abnormal loading conditions and coronary artery disease. They are classified into a number of morphological and functional phenotypes that can be caused by genetic and non-genetic mechanisms. The dominant themes in papers published in 2012-2013 are similar to those reported in Almanac 2011, namely, the use (and interpretation) of genetic testing, development and application of novel non-invasive imaging techniques and use of serum biomarkers for diagnosis and prognosis. An important innovation since the last Almanac is the development of more sophisticated models for predicting adverse clinical events.Heart (British Cardiac Society) 03/2014; · 5.01 Impact Factor
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ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac entity characterized by right ventricular, or biventricular, fibrofatty replacement of myocardium. Structural alterations may lead to sudden cardiac death, mainly in young males during exercise. Autosomal dominant pattern of inheritance is reported in most parts of pathogenic genetic variations identified. Currently, 13 genes have been associated with the disease but nearly 40 % of clinically diagnosed cases remain without a genetic diagnosis. New genetic technologies allow further genetic analysis, generating a significant amount of genetic data in novel genes, which is often classified as of ambiguous significance. We focus on genetic advances of arrhythmogenic right ventricular cardiomyopathy, helping clinicians to interpret and translate genetic data into clinical practice.Clinical research in cardiology : official journal of the German Cardiac Society. 11/2014;
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ABSTRACT: In a series of recent reports, mutations in the gene encoding a protein called LUMA (or TMEM43), widely speculated to be a tetraspan transmembrane protein of the nuclear envelope, have been associated with a specific subtype of cardiomyopathy (arrhythmogenic cardiomyopathies) and cases of sudden death. However, using antibodies of high specificity in immunolocalization experiments, we have discovered that, in mammals, LUMA is a component of zonula adhaerens and punctum adhaerens plaques of diverse epithelia and epithelial cell cultures and is also located in (or in some species associated with) the plaques of composite junctions (CJs) in myocardiac intercalated disks (IDs). In CJs, LUMA often colocalizes with several other CJ marker proteins. In all these cells, LUMA has not been detected in the nuclear envelope. Surprisingly, under certain conditions, similar CJ localizations have also been seen with some antibodies commercially available for some time. The identification of LUMA as a plaque component of myocardiac CJs leads to reconsiderations of the molecular composition and architecture, the development, the functions, and the pathogenic states of CJs and IDs. These findings now also allow the general conclusion that LUMA has to be added to the list of mutations of cardiomyocyte junction proteins that may be involved in cardiomyopathies.Cell and Tissue Research 04/2014; · 3.68 Impact Factor