Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2)

TLDR

Arrhythmogenic right ventricular dysplasia type 2 is an autosomal dominant cardiomyopathy marked by right‑ventricular degeneration, electrical instability, and sudden death, and involves the cardiac ryanodine receptor (RyR2), a Ca²⁺‑activated channel homologous to the skeletal muscle RyR1 and implicated in malignant hyperthermia and central core disease. The study aimed to physically map the critical ARVD2 region, exclude actinin‑2 and nidogen as candidates, characterize the genomic structure of RYR2, and identify RYR2 mutations in affected families. Researchers performed physical mapping of the ARVD2 locus, excluded actinin‑2 and nidogen, mapped the genomic structure of RYR2, and screened four families for RYR2 mutations. The ARVD2 locus was mapped to chromosome 1q42–q43, and mutations in two highly conserved regions of RYR2—corresponding to MH/CCD mutation hotspots—were identified in four families, enabling pre‑symptomatic carrier detection.

Abstract

Arrhythmogenic right ventricular dysplasia type 2 (ARVD2, OMIM 600996) is an autosomal dominant cardiomyopathy, characterized by partial degeneration of the myocardium of the right ventricle, electrical instability and sudden death. The disease locus was mapped to chromosome 1q42–q43. We report here on the physical mapping of the critical ARVD2 region, exclusion of two candidate genes (actinin 2 and nidogen), elucidation of the genomic structure of the cardiac ryanodine receptor gene (RYR2) and identification of RYR2 mutations in four independent families. In myocardial cells, the RyR2 protein, activated by Ca2+, induces the release of calcium from the sarcoplasmic reticulum into the cytosol. RyR2 is the cardiac counterpart of RyR1, the skeletal muscle ryanodine receptor, involved in malignant hyperthermia (MH) susceptibility and in central core disease (CCD). The RyR2 mutations detected in the present study occurred in two highly conserved regions, strictly corresponding to those where mutations causing MH or CCD are clustered in the RYR1 gene. The detection of RyR2 mutations causing ARVD2, reported in this paper, opens the way to pre-symptomatic detection of carriers of the disease in childhood, thus enabling early monitoring and treatment.