A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
In conclusion, these additional three CASQ2CPVT families suggest that CASQ2 mutations are more common than previously thought and produce a severe form of CPVT.
These data, combined with our previous findings, show that RYR2 mutations are present in at least 6/16 (38%) of the catecholaminergic polymorphic ventricular tachycardia families, while CASQ2 mutations must be a rare cause of CPVT.
Mutations in human cardiac calsequestrin (CASQ2), a high-capacity calcium-binding protein located in the sarcoplasmic reticulum (SR), have recently been linked to effort-induced ventricular arrhythmia and sudden death (catecholaminergic polymorphic ventricular tachycardia).
A missense mutation in CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2) genes.
Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel and in CASQ2-encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively).
The same deletion was also identified in association with a novel point mutation (CASQ2(L167H)) in a highly symptomatic CPVT child who is the first CPVT patient carrier of compound heterozygous CASQ2 mutations.
Functional characterization of mutations identified in the RyR2 and CASQ2 genes has demonstrated that CPVT are caused by derangements of the control of intracellular calcium.
Furthermore, two CPVT-inducing CASQ2 mutations, which cause mechanistically different defects in CASQ2 and RyR2 function, lead to increased diastolic SR Ca release events and exhibit a similar CPVT disease phenotype.
Interestingly CPVT has been linked to mutations in genes encoding the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2): two fundamental proteins involved in regulation of intracellular Ca(2+) in cardiac myocytes.
The disease has a heterogeneous genetic basis, with mutations in the cardiac Ryanodine Receptor channel (RyR2) gene accounting for an autosomal-dominant form (CPVT1) in approximately 50% and mutations in the cardiac calsequestrin gene (CASQ2) accounting for an autosomal-recessive form (CPVT2) in up to 2% of CPVT cases.
Autosomal dominant and recessive forms of CPVT because of mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin 2 (CASQ2) have been reported.
These in vitro and in silico data suggest a regulatory role of CASQ2 on cytosolic Ca(2+) and hERG channels which may contribute to the etiology of CPVT.
We additionally investigated how CPVT (catecholaminergic polymorphic ventricular tachycardia) mutations affect CASQ2 structure and its molecular behaviour when exposed to different metal ions.