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DSG2 Mutations Contribute to Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 08/2006; 79(1):136-42. DOI: 10.1086/504393
Source: PubMed

ABSTRACT Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a disorder characterized by fibrofatty replacement of cardiac myocytes that typically manifests in the right ventricle. It is inherited as an autosomal dominant disease with reduced penetrance, although autosomal recessive forms of the disease also occur. We identified four probands with ARVD/C caused by mutations in DSG2, which encodes desmoglein-2, a component of the cardiac desmosome. No association between mutations in this gene and human disease has been reported elsewhere. One of these probands has compound-heterozygous mutations in DSG2, and the remaining three have isolated heterozygous missense mutations, each disrupting known functional components of desmoglein-2. We report that mutations in DSG2 contribute to the development of ARVD/C.

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    • "The ICS region is required for DSG1 binding to plakoglobin through a 1:1 complex, with key hydrophobic residues involved having been mapped by alanine scanning mutagenisis [62] [63]. Missense mutations in the plakoglobin binding site including G812C, G812S, and C813R are known to be pathogenic [50] [64]. Surprisingly, these mutant DSG2 proteins display localizations, stabilities, and plakoglobin binding similar to the wild-type form and differ instead in their abilities to be posttranslationally modified and bind PKP2. "
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    • "The ICS region is required for DSG1 binding to plakoglobin through a 1:1 complex, with key hydrophobic residues involved having been mapped by alanine scanning mutagenisis [62] [63]. Missense mutations in the plakoglobin binding site including G812C, G812S, and C813R are known to be pathogenic [50] [64]. Surprisingly, these mutant DSG2 proteins display localizations, stabilities, and plakoglobin binding similar to the wild-type form and differ instead in their abilities to be posttranslationally modified and bind PKP2. "
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    • "ation into desmosomal junctions [ Posthaus et al . , 2003 ] . The R - X - R / K - R ( amino acids 46 – 49 ) recognition site for the proprotein convertase furin is a highly conserved part of the DSG2 proprotein [ Adzhubei et al . , 2010 ] . Point mutations in this furin cleavage site in DSG2 have commonly been reported in ARVC patients worldwide [ Awad et al . , 2006 ; Tan et al . , 2010 ; van der Zwaag et al . , 2009 ] ."
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