Alternative titles; symbols
HGNC Approved Gene Symbol: RYR2
Cytogenetic location: 1q43 Genomic coordinates (GRCh38): 1:237,042,184-237,833,988 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q43 | Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome | 115000 | Autosomal dominant | 3 |
| Ventricular tachycardia, catecholaminergic polymorphic, 1 | 604772 | Autosomal dominant | 3 |
RYR2 is the major Ca(2+) channel protein in the membrane of the sarcoplasmic reticulum (SR). SR acts as an intracellular Ca(2+) storage in cardiomyocytes, and Ca(2+) can be released from SR to the cytosol by RYR2 (Polonen et al., 2018).
Otsu et al. (1990) cloned a cDNA encoding the calcium-release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum.
Zorzato et al. (1990) cloned human RYR2 that encodes a 5,032-amino acid protein with a calculated molecular mass of 563.5 kD, which is made without an N-terminal signal sequence. Analysis of RYR2 sequence indicates that 10 potential transmembrane sequences in the C-terminal fifth of the molecule and 2 additional potential transmembrane sequences nearer to the center of the molecule could contribute to the formation of the Ca(2+) conducting pore. The remainder of the molecule is hydrophilic and presumably constitutes the cytoplasmic domain of the protein.
Tiso et al. (2001) determined that the RYR2 gene encompasses 105 exons.
Otsu et al. (1990) located the human cardiac ryanodine receptor on chromosome 1 by analysis of rodent/human somatic cell hybrids. By fluorescence in situ hybridization, Otsu et al. (1993) demonstrated that the RYR2 gene is located in the interval between 1q42.1 and 1q43. Mattei et al. (1994) used in situ hybridization to map the murine Ryr2 gene to 13A1-13A2.
Crystal Structure
Tung et al. (2010) showed the 2.5-angstrom resolution crystal structure of a region spanning 3 domains of ryanodine receptor type 1 (RyR1; 180901), encompassing amino acid residues 1-559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kD cytoplasmic vestibule around the 4-fold symmetry axis. Tung et al. (2010) pinpointed the exact locations of more than 50 disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into 3 groups: those that destabilize the interfaces between the 3 amino-terminal domains, disturb the folding of individual domains, or affect 1 of the 6 interfaces with other parts of the receptor. Tung et al. (2010) proposed a model whereby the opening of RyR coincides with allosterically couples motions within the N-terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. Tung et al. (2010) proposed that the crystal structure provides a framework to understand the many disease-associated mutations in RyRs that have been studied using functional methods, and would be useful for developing new strategies to modulate RyR function in disease states.
Cryoelectron Microscopy
Gong et al. (2019) revealed the regulatory mechanism by which porcine RyR2 is modulated by human calmodulin (see 114180) through the structural determination of RyR2 under 8 conditions by cryoelectron microscopy. Apo-calmodulin and Ca(2+)-calmodulin bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical, and central domains. The shift in calmodulin-binding sites on RyR2 is controlled by Ca(2+) binding to calmodulin, rather than to RyR2. Ca(2+)-calmodulin induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95- and Ca(2+)-activated channel. In contrast, the pore of the ATP-, caffeine-, and Ca(2+)-activated channel remains open in the presence of Ca(2+)-calmodulin, which suggests that Ca(2+)-calmodulin is one of the many competing modulators of RyR2 gating.
The ryanodine receptor on the sarcoplasmic reticulum is the major source of calcium required for cardiac muscle excitation-contraction coupling. The channel is a tetramer composed of 4 RYR2 polypeptides and 4 FK506-binding proteins (see FKBP12.6, or FKBP1B; 600620). Marx et al. (2000) showed that protein kinase A (PKA; see 176911) phosphorylation of RYR2 dissociates FKBP12.6 and regulates the channel open probability. Using cosedimentation and coimmunoprecipitation, the authors defined a macromolecular complex composed of RYR2, FKBP12.6, PKA, the protein phosphatases PP1 (see 603771) and PP2A (see 603113), and an anchoring protein, AKAP6 (604691). In failing human hearts, Marx et al. (2000) showed that RYR2 is PKA hyperphosphorylated, resulting in defective channel function due to increased sensitivity to calcium-induced activation.
Using a quantitative yeast 2-hybrid system, Tiso et al. (2002) analyzed and compared the interaction between FKBP12.6 and 3 mutated FKBP12.6 binding regions. An RYR2 mutation (R2474S, 180902.0002) causing catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772) markedly increased the binding of RYR2 to FKBP12.6, whereas other RYR2 mutations (N2386I, 180902.0005; Y2392C) significantly decreased this binding. Tiso et al. (2002) suggested that the latter mutations increase RYR2-mediated calcium release to the cytoplasm, whereas others do not significantly affect cytosolic calcium levels, and that this might explain the clinical differences among patients.
In animals with heart failure and in patients with inherited forms of exercise-induced sudden cardiac death, depletion of the channel-stabilizing protein calstabin-2 (FKBP1B) from the ryanodine receptor-calcium release channel complex causes an intracellular calcium leak that can trigger fatal cardiac arrhythmias. Wehrens et al. (2004) found that a derivative of 1,4-benzothiazepine increased the affinity of calstabin-2 for RYR2, which stabilized the closed state of RYR2 and prevented the calcium leak that triggers arrhythmias. Wehrens et al. (2004) postulated that enhancing the binding of calstabin-2 to RYR2 may be a therapeutic strategy for common ventricular arrhythmias.
Wehrens et al. (2003) found that during exercise, RYR2 phosphorylation by PKA partially dissociated FKBP12.6 from the RYR2 channel, increasing intracellular Ca(2+) release and cardiac contractility. Fkbp12.6 -/- mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that caused sudden cardiac death. Mutations in RYR2 linked to exercise-induced arrhythmias in patients with CPVT, also known as stress-induced polymorphic ventricular tachycardia, reduced the affinity of FKBP12.6 for RYR2 and increased single-channel activity under conditions that simulated exercise. These data suggested that 'leaky' RYR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.
Jiang et al. (2003) characterized several rabbit Ryr3 (180903) splice variants. One variant lacking a predicted transmembrane helix formed a heteromeric channel with Ryr2 when coexpressed in HEK293 cells and had a dominant-negative effect on Ryr2 channel activity.
Lehnart et al. (2004) reviewed the RYR2-FKBP1B interaction and its role in heart failure and genetic forms of arrhythmias.
In experimentally induced failing hearts of beagle dogs, Yamamoto et al. (2008) previously demonstrated that defective interdomain interaction between the N-terminal domain (residues 1 to 600) and the central domain (residues 2000 to 2500) resulted in domain unzipping, Ca(2+) leak through the Ryr2 channel, and both cAMP-dependent hyperphosphorylation and Fkbp12.6 dissociation of Ryr2. Further studies showed that K201, a 1,4-benzothiazepine derivative, bound to residues 2114 to 2149, and that K201 interrupted interaction of domain(2114-2149) with residues 2234 to 2750, which appeared to mediate stabilization of Ryr2 and inhibit Ca(2+) leak.
In affected members of 2 large multiply consanguineous Amish families with exercise-associated syncope, cardiac arrest, or sudden unexplained death, Tester et al. (2020) identified homozygosity for a 344-kb tandem duplication (chr1:237,205,452-237,519,546, GRCh38) involving approximately 26,000 bp of intergenic sequence, the 5-prime UTR/promoter region of the RYR2 gene, and exons 1 through 4 of RYR2. The duplication segregated fully with disease in both families. Although a common ancestor was not identified despite pedigree expansion over several generations, the authors stated that the duplication likely represents a founder mutation in the Amish community. The authors noted that the phenotype did not appear to be distinct from autosomal dominant RYR2-mediated CPVT.
Ventricular Tachycardia, Catecholaminergic Polymorphic, 1
Stress-induced polymorphic ventricular tachycardia occurs in the structurally intact heart with onset of manifestations in childhood and adolescence. Affected individuals present with syncopal events and with a distinctive pattern of highly reproducible, stress-related, bidirectional ventricular tachycardia in the absence of either structural heart disease or a prolonged QT interval. Because this disorder had been shown to map to 1q42-q43, the same region as RYR2, and because of the likelihood that delayed afterdepolarizations underlie arrhythmia in this disorder, Priori et al. (2001) hypothesized that mutations in the RYR2 gene may be responsible. They studied 12 probands presenting with bidirectional ventricular tachycardia that was reproducibly induced by exercise stress testing and/or isoproterenol infusion and identified heterozygous missense mutations in 4 (see 180902.0001-180902.0004).
In 4 unrelated Italian families segregating autosomal dominant exercise-induced ventricular arrhythmias, Tiso et al. (2001) identified heterozygous missense mutations in the RYR2 gene (see, e.g., 180902.0005-180902.0006). The patients were originally diagnosed as having an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see 107970), with clinical findings that differed from those reported in other ARVD families (Bauce et al., 2000); the disorder was later designated to be catecholamine-induced ventricular tachycardia (Karmouch et al., 2018). The mutations occurred at highly conserved residues and segregated fully with disease in each family.
Priori et al. (2002) analyzed the RYR2 gene in 26 probands with CPVT in whom mutations had been excluded in the KCNQ1 (607542), KCNH2 (152427), SCN5A (600163), KCNE1 (176261), and KCNE2 (603796) genes and identified 9 different mutations in 10 probands, respectively (see, e.g., 180902.0001 and 180902.0010). With the inclusion of 4 previously reported mutation-positive families (Priori et al., 2001) in this study, Priori et al. (2002) found 9 family members who were RYR2 mutation carriers, 5 of whom had exercise-induced arrhythmias at clinical evaluation and 4 of whom were phenotypically silent (incomplete penetrance).
George et al. (2003) expressed 3 CPVT1-linked RYR2 mutations in a cardiomyocyte cell line. They found that phenotypic characteristics in resting cells expressing mutant RYR2 were indistinguishable from those expressing the wildtype. However, Ca(2+) release was augmented in cells expressing mutant RYR2 after RYR activation (caffeine or 4-chloro-m-cresol) or beta-adrenergic stimulation (isoproterenol). Interaction between RYR2 and FKBP1A remained intact after caffeine or 4-chloro-m-cresol activation, but was dramatically disrupted by isoproterenol or forskolin, both of which elevated cAMP to similar magnitudes in all cells and were associated with equivalent hyperphosphorylation of mutant and wildtype RYR2.
Similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias, are observed in Finnish families with stress-induced polymorphic ventricular tachycardia caused by a pro2328-to-ser (P2328S; 180902.0007), val4653-to-phe (V4653F; 180902.0008), or gln4201-to-arg (Q4201R; 180902.0009) mutation in the RYR2 gene. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the 'fight or flight' stress response. Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. All 3 RYR2 mutations exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, these mutants showed a significant gain-of-function defect consistent with leaky calcium release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. Lehnart et al. (2004) suggested that stabilization of the RYR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients.
Jiang et al. (2004) studied 3 mutations in the RYR2 gene linked to ventricular tachycardia and sudden death, including N4104K (180902.0003) and characterized their effects on store-overload-induced Ca(2+) release (SOICR) in human embryonic kidney cells. SOICR refers to the spontaneous Ca(2+) release that occurs when the sarcoplasmic reticulum store Ca(2+) content reaches a critical level. They demonstrated that the 3 mutations markedly increased the occurrence of SOICR. At the molecular level, they showed that these mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca(2+). Jiang et al. (2004) concluded that the increased sensitivity reduced the threshold for SOICR, thereby increasing the propensity for triggered arrhythmia.
Jiang et al. (2005) showed that CPVT/ARVD2-associated mutations throughout the RYR2 sequence enhanced the propensity for SOICR in HEK293 cells compared with wildtype. The same effect was observed in HL-1 cardiac cells for several of the mutations. Single RYR2 channel analysis revealed that the mutations augmented SOICR by primarily increasing channel sensitivity to luminal, but not cytosolic, Ca(2+) activation. Further analysis demonstrated that C-terminal RYR2 mutations did not alter Ca(2+) dependence of ryanodine binding to RYR2, and none of the mutations tested altered interaction of RYR2 with FKBP12.6.
In studies in HEK293 cells, Jiang et al. (2007) found that, in contrast to all other disease-linked RYR2 mutations characterized previously, the catecholaminergic idiopathic ventricular fibrillation-associated A4860G mutation (180902.0010) diminished the response of RYR2 to activation by luminal Ca(2+) but had little effect on the sensitivity of the channel to activation by cytosolic Ca(2+), and the transfected cells exhibited no SOICR. Jiang et al. (2007) concluded that loss of luminal Ca(2+) activation and SOICR activity can cause ventricular fibrillation and sudden death.
In affected individuals from 2 families with CPVT associated with sinoatrial and atrioventricular node dysfunction, atrial arrhythmias, and dilated cardiomyopathy, Bhuiyan et al. (2007) identified a heterozygous deletion of exon 3 of the RYR2 gene (180902.0011). The authors noted that these families expanded the phenotypic spectrum of human RYR2-related diseases.
Medeiros-Domingo et al. (2009) analyzed all 105 RYR2 exons using PCR, HPLC, and sequencing in 110 unrelated patients with a clinical diagnosis of CPVT and in 45 additional unrelated patients with an initial diagnosis of exercise-induced long QT syndrome (LQTS; see 192500) but who had a QTc of less than 480 ms and who were negative for mutation in 12 genes known to cause LQTS. The authors identified 63 possible CPVT1-associated mutations that were not found in 400 reference alleles in 73 (47%) of the 155 patients; 13 new mutation-containing exons were identified, with two-thirds of the patients having mutations in 1 of 16 exons. Three large genomic rearrangements involving exon 3 were detected in 3 unrelated cases. Medeiros-Domingo et al. (2009) stated that 45 of the 105 translated exons of the RYR2 gene were now known to host possible mutations, but that a tiered targeting strategy for CPVT should be considered, since approximately 65% of CPVT1-positive cases would be discovered by selective analysis of just 16 exons.
Using CPVT patient-specific induced pluripotent stem cell-derived cardiac muscle (iPSC-CM) cell lines carrying different RYR2 mutations, Polonen et al. (2018) evaluated the antiarrhythmic efficacy of carvedilol and flecainide. Adrenaline induced arrhythmias in all CPVT iPSC-CM cell lines examined, but it abolished arrhythmias in control cells. Both carvedilol and flecainide were equally effective in treating arrhythmias, as both drugs lowered intracellular Ca(2+) level and beating rate of cardiomyocytes significantly in all CPVT iPSC-CM cell lines. However, flecainide caused abnormal Ca(2+) transients in 61% of control cells compared with 26% of those treated with carvedilol. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca(2+) abnormalities, but they had the best response to drug therapies.
Ventricular Arrhythmias due to Cardiac Ryanodine Receptor Calcium Release Deficiency Syndrome
In 6 families in which the proband experienced sudden cardiac death (SCD) or aborted SCD (aSCD) resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for missense mutations in the RYR2 gene (see, e.g., 180902.0012-180902.0014). Combining these families with 4 previously reported families with RYR2 missense mutations, including a family studied by Priori et al. (2002) (180902.0010), revealed that 31 (67%) of 46 mutation carriers experienced SCD or aSCD, whereas none of the 46 mutation-negative individuals had life-threatening ventricular arrhythmias. All of the missense mutations showed loss-of-function effects, including marked suppression of caffeine-induced Ca(2+) release and increased threshold for store overload-induced Ca(2+) release and/or RYR2-mediated fractional Ca(2+) release, as well as impairment of cytosolic and luminal Ca(2+) activation of RYR2 channels in some cases. A knockin mouse model with the D4646A mutation (see 180902.0012) suggested that RYR2 loss-of-function mutations may cause ventricular arrhythmias via an early afterdepolarization-mediated mechanism.
Reviews
Benkusky et al. (2004) reviewed RYR1 and RYR2 mutations and their role in muscle and heart disease, respectively.
Takeshima et al. (1998) generated Ryr2 -/- mice, which died at approximately embryonic day 10 with morphologic abnormalities in the heart tube. Prior to embryonic death, large vacuolate sarcoplasmic reticula and structurally abnormal mitochondria began to develop in the mutant cardiac myocytes, and the vacuolate sarcoplasmic reticula appeared to contain high concentrations of Ca(2+). A Ca(2+) transient evoked by caffeine was abolished in mutant cardiac myocytes. Treatment with ryanodine did not exert a major effect on spontaneous Ca(2+) transients in control cardiac myocytes at embryonic days 9.5-11.5. Takeshima et al. (1998) proposed that RYR2 does not participate principally in Ca(2+) signaling during excitation-contraction coupling in the embryonic heart but functions as a major Ca(2+) leak channel to maintain the normal range of luminal Ca(2+) levels in the developing sarcoplasmic reticulum.
Jiang et al. (2002) characterized the properties of an R4496C mutation in mouse Ryr2, which is equivalent to the disease-causing human RYR2 mutation R4497C (180902.0004). Binding studies in HEK293 cells using tritium-labeled ryanodine revealed that the R4496C mutation resulted in an increase in RYR2 channel activity, particularly at low concentrations, and enhanced the sensitivity of RYR2 to activation by Ca(2+) and by caffeine. HEK293 cells transfected with R4496C Ryr2 displayed spontaneous Ca(2+) oscillations more frequently than cells transfected with wildtype Ryr2. Substitution of a negatively charged glutamate for the positively charged R4496 further enhanced basal channel activity, whereas replacement of R4496 by a positively charged lysine had no significant effect on basal activity. Jiang et al. (2002) concluded that charge and polarity at residue 4496 play an essential role in RYR2 channel gating, and that enhanced basal activity of RYR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia.
Wehrens et al. (2006) generated transgenic mice with a ser2808-to-ala substitution (S2808A) of the Ryr2 gene. In vitro and in vivo studies showed that the Ryr2 alanine-2808 channels could not be phosphorylated by protein kinase A, indicating that serine-2808 is the dominant functional phosphorylation site on Ryr2 channels. Transgenic mice with heart failure induced by ligation of the left anterior descending artery showed a higher ejection fraction and improved cardiac function compared to wildtype mice with induced heart failure. Wehrens et al. (2006) concluded that PKA-mediated hyperphosphorylation of serine-2808 on the Ryr2 channel is a critical mediator of progressive cardiac dysfunction after myocardial infarction.
Kannankeril et al. (2006) generated mice heterozygous for the human disease-associated arg176-to-gln (R176Q) mutation in the Ryr2 gene and observed no fibrofatty infiltration or structural abnormalities characteristic of arrhythmogenic right ventricular dysplasia, but right ventricular end-diastolic volume was decreased in the mutant mice compared to controls. Ventricular tachycardia was observed after caffeine and epinephrine injection in Ryr2 R176Q heterozygotes but not in wildtype mice. Isoproterenol administration during intracardiac programmed stimulation increased the number and duration of ventricular tachycardia episodes in mutants but not controls. Isolated cardiomyocytes from Ryr2 R176Q heterozygous mice exhibited a higher incidence of spontaneous Ca(2+) oscillations in the absence and presence of isoproterenol compared with controls. Kannankeril et al. (2006) suggested that the R176Q mutation in RYR2 predisposes the heart to catecholamine-induced oscillatory calcium-release events that trigger a calcium-dependent ventricular arrhythmia.
Lehnart et al. (2008) found that mice heterozygous for the human CPVT-associated mutation R2474S in Ryr2 exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with an Ryr2-specific compound that enhanced binding of calstabin-2 to the mutant receptor inhibited channel leak, prevented cardiac arrhythmias, and raised the seizure threshold. Lehnart et al. (2008) concluded that CPVT is a combined neurocardiac disorder in which leaky RYR2 channels in brain cause epilepsy and in heart cause exercise-induced sudden death.
Zhao et al. (2015) found that hearts from knockin mice heterozygous for the Ryr2 A4860G mutation expressed Ryr2 protein at the same level as wildtype and showed no cardiac structural alterations or major hemodynamic parameters. However, heterozygous mutant mice exhibited basal bradycardia, and no homozygote mutants were detected at birth, suggesting a lethal phenotype. Sympathetic stimulation elicited malignant arrhythmias in heterozygous mutant hearts, recapitulating the main proarrhythmogenic features reported in a human patient with the same mutation. In isoproterenol-stimulated ventricular myocytes, the A4860G mutation decreased the peak of Ca(2+) release during systole, gradually overloading the sarcoplasmic reticulum with Ca(2+). The resultant Ca(2+) overload then randomly caused bursts of prolonged Ca(2+) release, activating electrogenic Na(+)-Ca(2+) exchanger activity and triggering early afterdepolarizations.
Shan et al. (2012) found that 3 knockin mouse lines heterozygous for the CPVT-linked Ryr2 mutations R2474S, R2386I, or L433P (180902.0006) displayed atrial burst pacing-induced atrial fibrillation (AF) due to increased diastolic SR Ca(2+) leak in atrial myocytes compared with wildtype. Increased diastolic SR Ca(2+) leak in atrial myocytes from mice heterozygous for R2474S was associated with Ryr2 oxidation and decreased Fkbp12.6 binding to Ryr2. Only atrial, and not ventricular, burst pacing increased resting diastolic SR Ca(2+) leak and induced arrhythmias in R2474S-heterozygous mice. The small molecule Rycal S107 stabilized Ryr2-Fkbp12.6 interactions in the channel complex by inhibiting oxidation/phosphorylation of Ryr2 and significantly decreased the diastolic SR Ca(2+) leak in R2474S-heterozygous mice at the cellular level and prevented burst pacing-induced AF in vivo. Fkbp12.6-knockout mice showed increased atrial burst pacing-induced AF, but it was not prevented by S107 treatment, indicating that the action of S107 was dependent on the presence of Fkbp12.6. The authors found that Camk2 (see 114078) phosphorylation of Ryr2 did not play a pivotal role in atrial burst pacing-induced AF, and that activation of sympathetic system did not appear to play an important role in triggering AF in CPVT mice.
Priori et al. (2001) identified a heterozygous ser2246-to-leu (S2246L) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). The boy had had recurrent syncopal events since the age of 3 years. The events were invariably induced by exercise. Resting ECG of the proband was normal. Ventricular arrhythmias (isolated premature ventricular beats, couplets, and runs of bidirectional ventricular tachycardia) could be reproducibly induced during exercise testing and progressively worsened as the workload increased. Electrical stimulation induced no repetitive arrhythmias, but isoproterenol infusion induced bidirectional ventricular tachycardia. The patient was treated with nadolol, and an implantable cardiac defibrillator was implanted.
In a male patient with bidirectional ventricular tachycardia who developed symptoms of CPVT at 2 years of age, Priori et al. (2002) identified a de novo S2246L mutation in the RYR2 gene.
Priori et al. (2001) identified a heterozygous arg2474-to-ser (R2474S) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). The boy had had repeated syncopal episodes. His identical twin had a history of repeated syncopal events and died suddenly at 7 years of age; autopsy failed to demonstrate abnormal findings, and death was attributed to cardiac arrest. The parents were asymptomatic. The patient was treated with atenolol, and adequate control of the arrhythmias was achieved with no recurrence of syncope through 6 years of follow-up.
Priori et al. (2001) identified a heterozygous asn4104-to-lys (N4104K) mutation of the RYR2 gene in a 14-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). The boy had been referred because of frequent episodes of loss of consciousness during exercise, beginning at age 7 years. There was no family history of sudden cardiac death and/or syncopal episodes. The parents were asymptomatic, with normal hearts and no exercise-induced arrhythmias. The patient was treated with atenolol, which prevented recurrence of syncope and ventricular arrhythmias during 9 years of follow-up.
Priori et al. (2001) identified a heterozygous arg4497-to-cys (R4497C) mutation of the RYR2 gene in a 30-year-old woman with catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772) and a family history of sudden cardiac death. Testing showed bidirectional ventricular tachycardia developing during exercise stress testing in the woman, her mother, in 2 of her sisters, and in her brother; 2 other sisters had died at ages 14 and 16 years, respectively, one while being tested at school and the second while climbing stairs. During 1 year of follow-up after placement of an implantable cardiac defibrillator, the patient experienced 2 appropriate shocks that successfully terminated ventricular fibrillation. On both occasions, emotional stress preceded the events; the first episode occurred while she was being fired by her boss; the second while she was acting in a play at the local school.
In two 3-generation families (families 102 and 123) with exercise-induced ventricular arrhythmias (CPVT1; 604772), one of which (102) was originally reported by Rampazzo et al. (1995), Tiso et al. (2001) detected a 7157A-T transversion in exon 47 of the RYR2 gene, resulting in an asn2386-to-ile (N2386I) mutation at a highly conserved residue in the 12-kD FK506-binding domain. The mutation segregated fully with disease in both families and was not found in 120 healthy Italian controls. Both families were from Monselice, a small town close to Padua, and haplotype analysis suggested the existence of a relatively recent common ancestor for the 2 apparently independent families. The phenotype, which was originally diagnosed as an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see 107970), was later designated to be catecholamine-induced ventricular tachycardia (Karmouch et al., 2018).
In a 3-generation family (family 122) with exercise-induced ventricular arrhythmias (CPVT1; 604772), Tiso et al. (2001) detected a T-to-C transition at nucleotide 1298 in exon 15 of the RYR2 gene, resulting in a leu433-to-pro (L433P) substitution at a highly conserved residue in the cytosolic portion of the protein. The L433P variant segregated fully with disease in the family and was not found in 120 healthy Italian controls. The authors noted that the affected family members also carried a known RYR2 polymorphism, G1885E, on the same allele as the L433P variant. The phenotype, which was originally diagnosed as an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see 107970), was later designated to be catecholamine-induced ventricular tachycardia (Karmouch et al., 2018).
Olubando et al. (2020) reviewed mutations according to ACMG criteria and considered the L33P mutation to be a variant of uncertain significance (1 strong, 1 moderate, and 1 supporting).
Laitinen et al. (2001) reported a pro2328-to-ser (P2328S) missense mutation in the RYR2 gene in a large Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; 604772) and sudden unexplained death. This mutation was located in the large cytoplasmic domain of the cardiac ryanodine receptor.
Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The P2328S mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function.
Laitinen et al. (2001) reported a val4653-to-phe (V4653F) mutation in the RYR2 gene in a large Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; 604772) and sudden unexplained death. This mutation was located in the carboxy-terminal part of the cardiac ryanodine receptor, which contains several membrane-spanning domains.
Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The V4653F mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function.
Laitinen et al. (2001) reported a gln4201-to-arg (Q4201R) mutation in the RYR2 gene in a Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; 604772) and sudden unexplained death. This mutation was located in the C-terminal part of the RYR2 receptor, which contains several membrane-spanning domains.
Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The Q4201R mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function.
In a female patient with ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Priori et al. (2002) identified a heterozygous ala4860-to-gly (A4860G) substitution at a highly conserved transmembrane residue of the RYR2 gene. Her mother and a maternal uncle had unexplained sudden cardiac death at 38 years and 22 years of age, respectively; her sister was an asymptomatic carrier of the mutation. The mutation was not found in 350 unrelated controls.
In A4860G-transfected human embryonic kidney cells, Jiang et al. (2007) found that the mutation diminished the response of RYR2 to activation by luminal Ca(2+) but had little effect on the sensitivity of the channel to activation by cytosolic Ca(2+). Stable, inducible HEK293 cells expressing the A4860G mutant showed caffeine-induced Ca(2+) release but exhibited no store-overload-induced Ca(2+) release (SOICR), and HL1 cardiac cells transfected with the A4860G mutant displayed attenuated SOICR activity compared to cells transfected with wildtype RYR2. Jiang et al. (2007) concluded that loss of luminal Ca(2+) activation and SOICR activity can cause ventricular fibrillation and sudden death.
Using site-directed mutagenesis, Zhao et al. (2015) showed that the A4860G mutation in mouse Ryr2 did not affect the expression level of the protein, but it severely inhibited Ryr2 channel activity.
Sun et al. (2021) restudied the patient originally reported by Priori et al. (2002), noting that she had no trigger for her original event, which involved an aborted sudden cardiac death (aSCD) at age 7 years, with documented ventricular fibrillation. An exercise stress test performed 1 week after the event was unremarkable with no arrhythmias elicited; similarly, programmed electrical stimulation and isoproterenol administration did not induce arrhythmias. Sun et al. (2021) classified the patient as having RYR2 Ca(2+) release deficiency syndrome.
In affected individuals from 2 families with catecholaminergic polymorphic ventricular tachycardia associated with sinoatrial and atrioventricular node dysfunction, atrial arrhythmias, and dilated cardiomyopathy (CPVT1; 604772), Bhuiyan et al. (2007) identified a heterozygous 1.1-kb deletion comprising all of exon 3 and part of the flanking introns 2 and 3 (161-236_272+781del1126) of the RYR2 gene, resulting in loss of 35 amino acids. Several patients in both families gradually developed depressed left ventricular function, and 1 patient who died suddenly at 30 years of age had left ventricular dilation on echocardiography. At autopsy, myocardial biopsy of the left interventricular septum showed mild myocyte hypertrophy and interstitial fibrosis; there were no inflammatory or fibrolipomatous changes of the right ventricular endocardium.
Medeiros-Domingo et al. (2009) identified 3 large genomic rearrangements comprising exon 3 of the RYR2 gene in 3 unrelated patients with CPVT1, involving a 3.6-kb deletion in 1 case and a 1.1-kb deletion in 2 cases.
In a 3-generation family with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for a c.13937A-C transversion in exon 96 of the RYR2 gene, resulting in an asp4646-to-ala (D4646A) substitution. The 51-year-old proband experienced syncope and aborted SCD at age 39 years, with ventricular fibrillation observed on the ambulance monitor. In the ICU, polymorphic ventricular tachycardia was observed and treated with direct-current (DC) shock. No arrhythmias were elicited on exercise stress test, and she underwent placement of an implantable cardioverter-defibrillator (ICD), which later discharged appropriately when she experienced syncope during an episode of acute emotional stress. Family history revealed 4 more cases of SCD in the maternal branch of the family, occurring between 16 and 43 years of age, triggered by acute emotional stress. The D4646A mutation was found in a maternal aunt who died with SCD, as well as in the proband's asymptomatic 17-year-old son and in an asymptomatic first cousin once removed whose father and paternal grandfather both had SCD, but the variant was not present in the proband's asymptomatic sister or in 3 asymptomatic male cousins. Functional analysis demonstrated that the D4646A mutation markedly suppressed caffeine-induced Ca(2+) release and store overload-induced Ca(2+) release (SOICR) without altering the store capacity. In addition, the SOICR termination threshold and RYR2-mediated fractional Ca(2+) release were both significantly increased with the mutant compared to wildtype RYR2. The D4646A mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels. The authors generated a knockin mouse model and observed that the D4646A mutation abolished abnormal diastolic spontaneous Ca(2+) release from the sarcoplasmic reticulum in intact mouse hearts, completely protecting them against delayed afterdepolarization-driven ventricular arrhythmias. There was substantial electrophysiologic remodeling in the mutant mouse hearts, increasing the transient outward K+ current, the L-type Ca(2+) channel current, and the Na+/Ca(2+) exchange current. This altered the action potential waveform (shortened APD50 and lengthened APD90) and increased the propensity for arrhythmogenic early afterdepolarizations in the mutant hearts.
In a 3-generation family with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for a c.11983A-C transversion in the RYR2 gene, resulting in an ile3995-to-val (I3995V) substitution. The variant was initially identified in the family after 2 cousins had SCD at ages 28 and 32 years. The 60-year-old female proband was a known carrier of the I3995V mutation who experienced syncope at age 52 while watching television. Cardiac evaluation, including an exercise stress test, was negative, but given the family history, an implantable cardioverter-defibrillator (ICD) was placed. The device recorded nonsustained polymorphic ventricular tachycardia/ventricular fibrillation during follow-up, when proband had presyncopal episodes. Her brother and her 2 children were asymptomatic carriers of the variant. Functional analysis demonstrated that the I3995V mutation markedly suppressed caffeine-induced Ca(2+) release and store overload-induced Ca(2+) release (SOICR) without altering the store capacity. In addition, the SOICR termination threshold and RYR2-mediated fractional Ca(2+) release were both significantly increased with the mutant compared to wildtype RYR2. The I3995V mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels.
In 3 sibs with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for a c.12587C-T transition in the RYR2 gene, resulting in a thr4196-to-ile (T4196I) substitution. The proband had recurrent episodes of syncope on exertion at age 17 years, but cardiac evaluation was normal, including exercise stress testing. She died suddenly at age 19 while running. Cardiac screening of her 4 sibs, including exercise stress testing, was negative. However, 12 years later, the proband's 33-year-old sister collapsed while running on a treadmill and was found to be in ventricular fibrillation by paramedics, who performed successful cardioversion to normal sinus rhythm. Another brother later died suddenly while running during a baseball game. The remaining 2 sibs and the 33-year-old sister's 3 asymptomatic children did not carry the mutation. Functional analysis demonstrated that the T4196I mutation markedly suppressed caffeine- and store overload-induced Ca(2+) release without altering the store capacity. In addition, RYR2-mediated fractional Ca(2+) release was significantly increased with the mutant compared to wildtype RYR2. The T4196I mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels.
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