Mutation in Human Desmoplakin Domain Binding to Plakoglobin Causes a Dominant Form of Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVD/C) is a genetically heterogeneous disease characterized by progressive degeneration of the right ventricular myocardium and increased risk of sudden death. Here, we report on a genome scan in one Italian family in which the disease appeared unlinked to any of the six different ARVD loci reported so far; we identify a mutation (S299R) in exon 7 of desmoplakin (DSP), which modifies a putative phosphorylation site in the N-terminal domain binding plakoglobin. It is interesting that a nonsense DSP mutation was reported elsewhere in the literature, inherited as a recessive trait and causing a biventricular dilative cardiomyopathy associated with palmoplantar keratoderma and woolly hairs. Therefore, different DSP mutations might produce different clinical phenotypes, with different modes of inheritance.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a not so rare “disease of the desmosome” with multiple clinical presentations

“…Desmosomes serve as major cell-cell junctions, especially in epidermal cells and in cardiomyocytes 26 .The S299R mutation disrupts a protein kinase C phosphorylation site at the amino-terminal domain 28 . This phosphorylation site is important for the interaction with desmosomes at the plasma membrane side as well as for binding to plakoglobin.…”

Recurrent and founder mutations in the Netherlands

“…ARVC/D is familial in up to 50% of cases. 1,[8][9][10][11][12] Since the identification of mutations in the genes encoding the desmosomal proteins desmoplakin (DSP) 13 and plakophilin-2 (PKP2), [14][15][16][17] followed by mutations in desmocollin-2 (DSC2), 18 desmoglein-2 (DSG2) 19 and plakoglobin (JUP), 20 it has been recognised that ARVC/D is mainly a disorder of the cardiac desmosome (figure 2), a cell adhesion complex residing in the intercalated disk of cardiomyocytes. Comprehensive screening of these genes encoding the proteins of this complex leads to the identification of a pathogenic mutation in approximately 40 to 60% of ARVC/D patients.…”

The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy

“…3 Eight genes have been detected so far as being independently involved in the pathogenesis of the disease. Five of them encode major desmosomal proteins: plakoglobin (MIM *173325), 3,4 desmoplakin (MIM *125647), 5 plakophilin-2 (MIM *602861), 6 desmoglein-2 (MIM *125671) 7 and desmocollin-2 (MIM *125645). 8,9 The involvement of such genes led to the current idea that ARVC/D is a disorder caused mainly by defects in cell-cell adhesion.…”