Alternative titles; symbols
HGNC Approved Gene Symbol: CASQ2
Cytogenetic location: 1p13.1 Genomic coordinates (GRCh38): 1:115,700,021-115,768,714 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.1 | Ventricular tachycardia, catecholaminergic polymorphic, 2 | 611938 | Autosomal recessive | 3 |
Cardiac muscle sarcoplasmic reticulum (SR) contains a cardiac isoform of calsequestrin. See 114250 for the isoform in skeletal muscle. The CASQ2 protein serves as the major calcium ion reservoir within the sarcoplasmic reticulum of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor.
Di Barletta et al. (2006) noted that the CASQ2 gene contains 11 exons.
By fluorescence in situ hybridization, Otsu et al. (1993) mapped the CASQ2 gene to chromosome 1p13.3-p11.
In affected members of 7 consanguineous Bedouin families in Israel segregating an autosomal recessive form of catecholamine-induced polymorphic ventricular tachycardia (CPVT2; 611938), Lahat et al. (2001) identified a mutation in a highly conserved region of the CASQ2 gene (D307H; 114251.0001). The mutation converts a negatively charged aspartic acid into a positively charged histidine in a highly negatively charged domain, and was thought to exert its deleterious effect by disrupting Ca(2+) binding.
Di Barletta et al. (2006) analyzed the CASQ2 gene in 2 unrelated probands with catecholamine-induced PVT and identified homozygosity for a 16-bp deletion (114251.0002) and compound heterozygosity for the 16-bp deletion and a missense mutation (114251.0003), respectively. In vitro characterization of both mutants showed reduction of active SR Ca(2+) release and calcium content; mutant CASQ2 containing the 16-bp deletion also showed altered calcium-binding properties and led to delayed afterdepolarizations.
Knollmann et al. (2006) generated Casq2-null mice which were viable and displayed normal release of Ca(2+) from the sarcoplasmic reticulum (SR) and contractile function under basal conditions. The mutant mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 (see 603283) and junctin (600582). Exposure to catecholamines in Casq2-null myocytes caused increased diastolic SR Ca(2+) leak, resulting in premature spontaneous SR Ca(2+) releases and triggered beats; in vivo, Casq2-null mice phenocopied the human arrhythmias. Knollmann et al. (2006) concluded that whereas functional SR Ca(2+) storage and thus cardiac contractility are maintained in Casq2-null mice, lack of Casq2 causes increased diastolic SR Ca(2+) leak, resulting in susceptibility to catecholaminergic ventricular arrhythmias.
Song et al. (2007) generated mice homozygous for the human D307H mutation or a CASQ2-null mutation and observed identical consequences for both: young mutant mice had structurally normal hearts but stress-induced ventricular arrhythmias, and aging produced cardiac hypertrophy and reduced contractile function. Mutant myocytes had reduced Casq2 and increased calreticulin (109091) and ryanodine receptor-2 (RYR2; 180902) but unchanged calstabin (FKBP1B; 600620), as well as reduced total SR Ca(2+), prolonged Ca(2+) release, and delayed Ca(2)+ reuptake. Stress further diminished Ca(2+) transients, elevated cytosolic Ca(2+), and triggered frequent, spontaneous SR Ca(2+) release. Treatment with Mg(2+), a ryanodine receptor inhibitor, normalized myocyte Ca(2+) cycling and decreased CPVT in mutant mice, indicating that Ryr2 dysfunction was critical to mutant Casq2 pathophysiology.
Paolini et al. (2011) found that mice lacking both Casq1 (114250) and Casq2 (Casq-null mice) presented with reduced body mass. Casq-null soleus fibers, but not extensor digitorum longus (EDL) fibers, showed ultrastructural changes. Twitch time kinetics were prolonged in both isolated Casq-null soleus and EDL muscle, but tension was not reduced. When stimulated for 2 seconds at 100 Hz, Casq-null soleus muscle, but not Casq-null EDL muscle, was able to sustain contraction. Paolini et al. (2011) concluded that slow fibers can function in the absence of CASQ because they require lower Ca(2+) amounts and slower cycling to function properly.
In affected members of 7 consanguineous Bedouin families in Israel segregating autosomal recessive catecholamine-induced polymorphic ventricular tachycardia (CPVT2; 611938), Lahat et al. (2001) identified homozygosity for a 1038G-C transversion in exon 9 of the CASQ2 gene, resulting in an asp307-to-his (D307H) substitution at a highly conserved residue. The mutation was not found in 350 Israeli Jewish, Arab, and Bedouin controls.
In a 6-year-old boy with catecholaminergic polymorphic ventricular tachycardia (CPVT2; 611938), di Barletta et al. (2006) identified homozygosity for a 16-bp deletion (339del16) in exon 3 of the CASQ2 gene, predicted to generate a frameshift and result in a stop codon 5 amino acids downstream. Asymptomatic family members were found to be heterozygous carriers of the deletion; none of them developed ventricular arrhythmias during Holter or exercise stress test. Ca(2+) overlay experiments showed that CASQ2 containing the 16-bp deletion did not bind calcium. When expressed in rat myocytes, the 16-bp deletion-containing mutant decreased sarcoplasmic reticulum Ca(2+) storing capacity and reduced the amplitude of I(Ca)-induced Ca(2+) transients and of spontaneous Ca(2+) sparks in permeabilized myocytes, although the effects observed with the 16-bp deletion were much more prominent than those with L167H (114251.0003) mutant. Mutant myocytes with the 16-bp deletion exposed to isoproterenol developed delayed afterpolarizations.
In a 17-year-old girl with catecholaminergic polymorphic ventricular tachycardia (CPVT2; 611938), di Barletta et al. (2006) identified compound heterozygosity for a leu167-to-his (L167H) substitution and the 16-bp deletion (114251.0002) in the CASQ2 gene. Her mother and maternal grandfather were asymptomatic carriers of the 16-bp deletion, whereas her father and 1 sister were asymptomatic carriers of the missense mutation. Ca(2+) overlay experiments showed that the L167H mutant had normal calcium-binding properties. When expressed in rat myocytes, however, the L167H mutant decreased sarcoplasmic reticulum Ca(2+) storing capacity and reduced the amplitude of I(Ca)-induced Ca(2+) transients and of spontaneous Ca(2+) sparks in permeabilized myocytes, although to a lesser extent than observed with the 16-bp deletion.
di Barletta, M. R., Viatchenko-Karpinski, S., Nori, A., Memmi, M., Terentyev, D., Turcato, F., Valle, G., Rizzi, N., Napolitano, C., Gyorke, S., Volpe, P., Priori, S. G. Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia. Circulation 114: 1012-1019, 2006. [PubMed: 16908766] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.623793]
Knollmann, B. C., Chopra, N., Hlaing, T., Akin, B., Yang, T., Ettensohn, K., Knollmann, B. E. C., Horton, K. D., Weissman, N. J., Holinstat, I., Zhang, W., Roden, D. M., Jones, L. R., Franzini-Armstrong, C., Pfeifer, K. Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca(2+) release, and catecholaminergic polymorphic ventricular tachycardia. J. Clin. Invest. 116: 2510-2520, 2006. [PubMed: 16932808] [Full Text: https://doi.org/10.1172/JCI29128]
Lahat, H., Pras, E., Olender, T., Avidan, N., Ben-Asher, E., Man, O., Levy-Nissenbaum, E., Khoury, A., Lorber, A., Goldman, B., Lancet, D., Eldar, M. 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. Am. J. Hum. Genet. 69: 1378-1384, 2001. [PubMed: 11704930] [Full Text: https://doi.org/10.1086/324565]
Otsu, K., Fujii, J., Periasamy, M., Difilippantonio, M., Uppender, M., Ward, D. C., MacLennan, D. H. Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes. Genomics 17: 507-509, 1993. [PubMed: 8406504] [Full Text: https://doi.org/10.1006/geno.1993.1357]
Paolini, C., Quarta, M., D'Onofrio, L., Reggiani, C., Protasi, F. Differential effect of calsequestrin ablation on structure and function of fast and slow skeletal muscle fibers. J. Biomed. Biotech. 2011: 634075, 2011. Note: Electronic Article. [PubMed: 21941434] [Full Text: https://doi.org/10.1155/2011/634075]
Song, L., Alcalai, R., Arad, M., Wolf, C. M., Toka, O., Conner, D. A., Berul, C. I., Eldar, M., Seidman, C. E., Seidman, J. G. Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia. J. Clin. Invest. 117: 1814-1823, 2007. [PubMed: 17607358] [Full Text: https://doi.org/10.1172/JCI31080]