They included a nonsense variant c.97C>T (p.R33*) and a missense variant c.748C>T (p.R250C) in Family 1 with three CPVT patients; two heterozygous frameshift variants, c.1074_1075delinsC (p.G359Afs*12) and c.1175_1178delACAG (p.D392Vfs*84), in Family 2 with one CPVT patient; one pathogenic homozygous variant c.98G>A (p.R33Q) of CASQ2 in the CPVT patient of Family 3; and two heterozygous splicing variants, (c.532+1G>A) and (c.838+1G>A), in Family 4 with one CPVT patient.
Induced pluripotent stem cells were generated from the whole blood of a 40-year-old woman with severe CPVT who is heterozygous for the p.Lys180ArgCASQ2 mutation.
To that end, we have designed a CaM protein (GSH-M37Q; dubbed as therapeutic CaM or T-CaM) that exhibited a slowed N-terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from CPVT mice carrying the CASQ2 mutation R33Q.
Approximately 50% of CPVT cases are caused by dominant mutations in the cardiac ryanodine receptor (RYR2) gene, <5% of cases are accounted for by recessive mutations in cardiac calsequestrin (CASQ2) or Triadin (TRDN).
Mutations in ryanodine receptor 2 (RyR2), a Ca<sup>2+</sup> release channel located in the sarcoplasmic reticulum (SR), or calsequestrin 2 (CASQ2), a SR Ca<sup>2+</sup> binding protein, are linked to CPVT.
The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein deficiency.
Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia.
Post-mortem molecular testing demonstrated this man to be heterozygous for a catecholaminergic polymorphic ventricular tachycardia (CPVT) associated mutation (Phe189Leu) in the calsequestrin 2 (CASQ2) gene.
Using confocal microscopy, we studied Ca2+ sparks and waves in isolated saponin-permeabilized ventricular myocytes from two CPVT mouse models (Casq2-/-, RyR2-R4496C+/-), wild-type (c57bl/6, WT) mice, and WT rabbits (New Zealand white rabbits).
LCSD conferred short-term suppression but less than optimal long-term suppression of exercise-induced ventricular arrhythmia among CASQ2-associated CPVT patients.
Electrocardiographic characteristics of VPCs during ST in 16 calsequestrin-2 (CASQ2) mutation carriers CPVT patients were compared with that in 36 healthy subjects.
Atrial overdrive pacing completely prevented VA in 16 of 19 (84%) Casq2(-/-) and in 7 of 8 (88%) RyR2(R4496C/+) mice and significantly reduced ventricular premature beats in both CPVT models (P<0.05).
In a consanguineous family, a novel homozygous CASQ2 mutation (p.L77P) was identified in a child with CPVT who required implantation of a cardioverter defibrillator due to episodes of syncope while on medical therapy.
In conclusion, patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective.
Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes.
Surprisingly, mutations in the gene encoding the cardiac isoform of calsequestrin (Casq2) have been associated with an inherited form of ventricular arrhythmia triggered by emotional or physical stress termed catecholaminergic polymorphic ventricular tachycardia (CPVT).
Because CASQ2 is a key player in excitation contraction coupling, the derangements in intracellular Ca(2+) handling may cause delayed afterdepolarizations (DADs), which constitute the mechanism underlying CPVT.
Here, we review the physiology of Casq2 in cardiac Ca2+ handling and discuss pathophysiological mechanisms that lead to CPVT caused by CASQ2 mutations.
Moreover, our report of the first splicing abnormalities in CASQ2 caused by intronic mutation or synonymous change underlines the absolute necessity to perform extensive molecular analysis for genetic diagnosis and counseling of CPVT.