Type OMIM Gene Locus Inheritance Notes<unk> 1 RYR2 1q42.1-q43 AD Ryanodine receptor—releases calcium from the sarcoplasmic reticulum<unk> 2 CASQ2 1p13.3-p11 AR Calsequestrin—calcium buffer within the sarcoplasmic reticulum<unk> 3 TECRL 7p22-p14 AR Trans-2,3-enoyl-CoA reductase-like protein—interacts with ryanodine receptors and calsequestrin<unk> 4 CALM1 14q32.11 AD Calmodulin—stabilises ryanodine receptors<unk> 5 TRDN 6q22.31 AR Triadin—forms complex with calsequestrin to interact with ryanodine receptors<unk>  can be caused by mutations in several genes, all of which are responsible for regulating the concentrations of calcium within cardiac muscle cells. The most commonly identified genetic mutation in<unk>  is a mutation in the RYR2 gene that encodes the cardiac ryanodine receptor, responsible for releasing calcium from the sarcoplasmic reticulum. Mutations associated with<unk>  have also been identified in the CASQ2 gene which encodes calsequestrin, a protein that binds calcium within the sarcoplasmic reticulum. Other genes associated with rarer, atypical forms of<unk>  include TECRL encoding Trans-2,3-enoyl-CoA reductase-like protein, CALM1, CALM2 and CALM3 all encoding Calmodulin, and TRDN encoding Triadin.<unk> 1: RYR2 mutations The most commonly identified genetic mutations in those suffering from<unk>  occur in the RYR2 gene which encodes the cardiac ryanodine receptor. Mutations in this gene lead to an autosomal dominant form of typical<unk>  known as<unk> 1. While the precise effect differs between specific mutations in this gene, many RYR2 mutations cause the ryanodine receptor to open in response to lower concentrations of calcium—the threshold for calcium release is lower. As a result, the sarcoplasmic reticulum spontaneously releases calcium through these abnormal ryanodine receptors when the concentration of calcium within the sarcoplasmic reticulum rises, a process known as store-overload induced calcium release. Sarcoplasmic reticulum calcium content increases in response to stimulation from catecholamines, explaining why arrhythmias in those with<unk>  occur at times when catecholamine levels are elevated. Some suggest that the increased sensitivity to calcium occurs only when the ryanodine receptor is phosphorylated by protein kinase A, while other suggest that the increased sensitivity also occurs under resting conditions. Two theories have been proposed for the underlying mechanism by which mutations in RYR2 promote store-overload induced calcium release: domain unzipping and FKBP12.6 unbinding. Domain unzipping refers to the separation of two important regions of the ryanodine receptor, the N-terminus and the central domain. Through this mechanism, a mutation might destabilise the ryanodine receptor's closed state and increase its sensitivity to calcium. A second potential mechanism involves the regulatory protein FKBP12.6, a protein that binds to and stabilises the ryanodine receptor. The binding of FKBP12.6 to the ryanodine receptor is regulated by phosphorylation. Phosphorylation by protein kinase A leads to the dissociation of FKBP12.6, rendering the ryanodine receptor more sensitive to cytosolic calcium. RYR2 mutations may interfere with the binding of FKB12.6 to the ryanodine receptor and thereby increase sensitivity to calcium. It is likely that FKBP12.6 plays a role in some<unk>  mutations but not others. RYR2 mutations responsible for<unk>  are mainly found in four major domains of the gene. Mutations affecting domains III and IV of the gene (corresponding to the N-terminal region of the protein and cytosolic linker respectively) occur in 46% of cases. Mutations are seen less frequently affecting domains I and II, both of which encode sections of the N-terminal region of the protein. RYR2 mutations associated with<unk>  that occur outside these four domains are very rare, being responsible for as few as 10% of reported cases. RYR2 mutations are most often missense mutations, such as single nucleotide substitutions causing one amino acid to be replaced by another, although in-frame substitutions and duplications have been described. More damaging nonsense mutations have not been reported in association with<unk> , potentially because these variants may lead to different cardiac diseases such as cardiomyopathies.<unk> 2: CASQ2 mutations Mutations in the CASQ2 gene are associated with an autosomal recessive form of typical<unk>  known as<unk> 2. This gene encodes calsequestrin, the major calcium-binding protein and calcium buffer within the sarcoplasmic reticulum. Mutations in CASQ2 account for only 3-5% of cases of<unk> . Fourteen mutations in CASQ2 have been identified in association with<unk> . Two of these are nonsense mutations causing the protein to be abnormally short, and two are deletion mutations, while ten are missense mutations that substitute one amino acid for another in the chain forming the protein. Mutations in CASQ2 cause a decrease in sarcoplasmic reticulum calcium-buffering capacity. This means that abrupt changes in sarcoplasmic total calcium will be buffered less and therefore translate to larger shifts in free calcium. The higher peaks in free calcium have greater potential to cause store-overload induced calcium release from the sarcoplasmic reticulum, leading to afterdepolarisations. In addition to its role as a calcium buffer, calsequestrin also regulates the release of calcium from the sarcoplasmic reticulum by directly modulating ryanodine receptors. When the concentration of calcium is low, calsequestrin monomers form a complex with the proteins triadin and junctin, which inhibit ryanodine receptors. However, at high calcium concentrations, calsequestrin forms polymers that dissociate from the ryanodine receptor channel complex, removing the inhibitory response and increasing the sensitivity of the ryanodine receptor to spontaneously releasing calcium. Decreased CASQ2 is also associated with high levels of calreticulin, a protein which among other roles regulates the reuptake of calcium into the sarcoplasmic reticulum by SERCA. In the absence of CASQ2, calreticulin levels increase and provide some compensatory calcium binding within the sarcoplasmic reticulum. It is possible that calreticulin may contribute to the generation of arrhythmias seen in association with CASQ2 mutations.
Catecholaminergic polymorphic ventricular tachycardia
Benign early repolarization
Junctional ectopic tachycardia
Brugada syndrome
Pre-excitation syndrome
Long QT syndrome
Wandering atrial pacemaker
Andersen–Tawil syndrome