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.

Figure 1

a, Twelve-lead ECG of patient III,9 (index case); presence of low voltages of QRS, QRS duration in V1-V2>V5-V6, negative T wave from V1 to V5. b, 2D-echocardiogram of the same patient (apical four-chamber view). Right ventricle (left of panel) is severely dilated, with trabecular disarrangement; left ventricle also appears to be affected.

Figure 2

Family tree, showing haplotypes for chromosome 6p24 markers (ordered from telomere to centromere). Filled squares or circles indicate affected individuals; shaded squares or circles indicate individuals still under investigation. The shared disease-associated haplotype is boxed. The critical region, identified by informative recombination events (indicated by X), occurred in individuals III,12, II,4, and III,13.

Figure 3

All investigated patients showed the presence of an additional band, visible on top of the electrophoretic pattern (arrow), in PCR amplicons of desmoplakin exon 7, once subjected to SSCP analysis. DNA sequencing of such amplicons revealed a C→G transition (codon 299, from AGC to AGG, resulting in a Ser→Arg substitution), which is present only in the affected members of the family. The lower band, detected by SSCP analysis in some individuals, corresponds to an additional polymorphism (I305F) identified in the same exon.

Figure 4

Alignment of the Z region from N-terminal domains of desmosomal members of the plakin family; protein names, GenBank accession numbers, and amino acid termini are reported on the right. A gray background indicates phylogenetic conservation of residues. Serine or threonine residues corresponding to putative PKC phosphorylation sites are shown in white characters on a black background. On the bottom, secondary structure (SS) consensus is shown (c = coil; h = helical) and its profile probability is reported (9, up to 100%; 8, up to 90%, and so on). The Ser residue, mutated in patients, is marked by an asterisk. This residue is central to a surface and acidic coiled region surrounded by two helices. This predicted PKC phosphorylation site is conserved in all phylogenetically related sequences: DPI (desmoplakin), BPAG1 (bullous pemphigoid antigen 1), PLEC1 (plectin), PPL (periplakin). Hs=Homo sapiens; Mm=Mus musculus; Rn=Rattus norvegicus; and Cg=Cricetulus griseus.