The disease mutation A77V in Ryanodine receptor RyR2 induces changes in energy conduction pathways in the protein

Energetically responsive residues of the 217 amino acid N-terminal domain of the cardiac Ryanodine receptor RyR2 are identified by a simple elastic net model. These residues lie along a hydrogen bonded path through the protein. The evolutionarily conserved residues of the protein are all located on this path or in its close proximity. All of the residues of the path are either located on the two Mir domains of the protein or are hydrogen bonded to them. Two calcium binding residues, E171 and E173, are proposed as potential binding residues, based on insights gained from the elastic net analysis of another calcium channel receptor, the inositol 1,4,5-triphosphate receptor, IP3R. Analysis of the disease causing A77V mutated RyR2 showed that the path is disrupted by the loss of energy responsiveness of certain residues. The cardiac Ryanodine receptor has become a subject of increasing interest as its role in the etiology of cardiac disease became more apparent. Two genetic diseases have been linked to mutations in the cardiac Ryanodine receptor: arrhythmogenic right ventricular dysplasia type 2 (ARVD/C Typ 2 or simply ARVD/C) and catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic ventricular tachycardia. ARVD/C is an autosomal dominant cardiomyopathy, characterized by partial degeneration of the myocardium of the right ventricle, electrical instability, and sudden death. ARVD/C and CPVT can be caused by mutations in the cardiac Ryanodine receptor 2 gene (RyR2), located on chromosome 1q42.1–q43. There is a familial occurrence in about 50%. ARVD/C is characterized by fibrofatty replacement, primarily of the right ventricle. The gold standard for ARVD/C diagnosis is the demonstration of this alteration of ventricular myocardium, either postmortem or at surgery [2]. In the past 10 years, the identification of causative mutations in plakoglobin, desmoplakin, plakophilin-2, desmoglein-2,and desmocollin-2 has fostered the view that ARVD/C is a disorder of the desmosome and provided insight into its pathogenesis. Desmosomal impairment followed by mechanical and electric uncoupling of cardiomyocytes leads to cell death with fibrofatty replacement. Two nondesmosomal genes have been associated with specific types of ARVD/C: patients with CPVT have mutations in the cardiac Ryanodine receptor gene. The prevalence of ARVD/C is unknown, it is thought to occur in six per 10,000 persons in certain populations. Some studies have suggested that it may be as common as 1/1,000, reaching up to 1/200 in carriers of mutations relevant to ARVD/C, accounting for up to 17% of all sudden cardiac deaths in the young. After hypertrophic heart disease, it is the number one cause of sudden cardiac death in young persons, especially athletes. The initial diagnosis of ARVD/C is based on the criteria established in 1994 and revised in 2010 including pathogenic mutations as a diagnostic criteria. After the diagnosis is made in one person, all of his or her first-degree relatives should be screened. N at ur e P re ce di ng s : h dl :1 01 01 /n pr e. 20 11 .6 67 8. 1 : P os te d 8 D ec 2 01 1