Ryanodine receptors and ventricular arrhythmias: Emerging trends in mutations, mechanisms and therapies

Evolution of Vertebrate Ryanodine Receptors Family in Relation to Functional Divergence and Conservation

“…For RyR2, the mutations within are associated with CPVT and ARVD2. [25][26][27]29,30) Previous results showed that the diseaseassociated mutations of RyR1 cluster were mainly located in three regions, 5,40,41) and four highly enriched ones for those in RyR2 clade, 31) however, we found that there were six related zones in RyR1 instead probably due to a large sample of mutated sites being discovered in this study. The mutation hot-spot regions within RyR3 have not been reported yet.…”

“…RyR2 was discovered as a candidate for Catecholaminergic polymorphic ventricular tachycardia 1 (CPVT1) and Arrhythmogenic right ventricular dysplasia 2 (ARVD2) in Human. 29,30) We also found 61 mutations in RyR2 in which the mutation sites clustered into four major regions, 31) and no mutations were discovered in regions of divergent sequences (DR1, DR2, and DR3). 5,32) All of these mutations were associated with CPVT1 ( Figure 4A).…”

Roles of the NH2-terminal Domains of Cardiac Ryanodine Receptor in Ca2+ Release Activation and Termination

“…The functional role of individual NH 2 -terminal domains of IP 3 R has been well studied. IBC-␤ and IBC-␣ are involved in IP 3 binding, whereas the SD is believed to clamp domains IBC-␤ and IBC-␣ in a conformation with reduced affinity for IP 3 , thus acting as a suppressor of IP 3 binding (20 -25). Interestingly, it has recently been shown that the IP 3 R SD and domain A of RyR are functionally interchangeable (20).…”

“…This RyR2-mediated sarcoplasmic reticulum Ca 2ϩ release also plays a critical role in the control of heart rhythm (1,2). Consistent with its fundamental role in cardiac function, naturally occurring mutations in RyR2 are associated with cardiac arrhythmias and cardiomyopathies (2)(3)(4)(5). Interestingly, most of the disease-associated RyR2 mutations are clustered in three hot spots in the linear sequence of the channel: the NH 2 -terminal, central, and COOH-terminal regions (5,6).…”

The role of genetic testing in unexplained sudden death

“…91 More than 100 mutations of RYR2 have been linked to CPVT1, the autosomal dominant form, which affect certain regions of the protein (mainly the FKBP12.6 binding domain, covering most RYR2). 93 Because of the large size of the gene, targeted screening has been used in the past and can potentially miss causative mutations. 94 Recent studies suggest that mutation location may be associated with severity of the phenotype, suggesting a future role for genetic risk stratification alongside conventional techniques.…”