Alternative titles; symbols
HGNC Approved Gene Symbol: CASQ1
Cytogenetic location: 1q23.2 Genomic coordinates (GRCh38): 1:160,190,575-160,201,886 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.2 | Myopathy, vacuolar, with CASQ1 aggregates | 616231 | Autosomal dominant | 3 |
Calsequestrin (CALQ), a high-capacity, moderate-affinity Ca(2+)-binding protein, is the main Ca(2+) buffer of the sarcoplasmic reticulum (SR) of cardiac and skeletal muscle. CASQ exists in 2 isoforms encoded by distinct genes: CASQ1, predominant in fast skeletal muscle fibers, and CASQ2 (114251), predominant in slow skeletal muscle fibers and in cardiac muscle (summary by Rossi et al., 2014).
Fujii et al. (1990) isolated a genomic clone for human fast-twitch skeletal muscle calsequestrin, which encoded a deduced 390 amino acid residues including a 28-residue N-terminal signal sequence. The mature 362-amino acid protein has a predicted mass of 41 kD. The protein shares significant homology with the rabbit fast-twitch muscle calsequestrin.
Bataille et al. (1994) cloned the human cDNA for calmitine, a mitochondrial calcium-binding protein specific for fast-twitch muscle fibers. Sequence analysis demonstrated that it was identical to the low affinity but high capacity calcium-binding protein from the sarcoplasmic reticulum, calsequestrin. Calmitine represents the Ca(2+) reservoir of mitochondria; calsequestrin may play a similar role in the sarcoplasmic reticulum.
Fujii et al. (1990) noted that the rabbit Casq1 gene has 11 exons and spans approximately 14 kb of genomic DNA. They found that the human CASQ1 gene also has 11 exons and shares 96% sequence identity with the rabbit gene.
By using a human-mouse somatic cell hybrid mapping panel, Fujii et al. (1990) assigned the CASQ1 gene to human chromosome 1.
By fluorescence in situ hybridization, Otsu et al. (1993) mapped the CASQ1 gene to 1q21.
Bataille et al. (1994) stated that calmitine is absent in patients with Duchenne and Becker types of muscular dystrophy and in dystrophic dy/dy mice.
In 7 members of 4 Italian families and in an unrelated Italian patient with vacuolar myopathy with CASQ1 aggregates (VMCQA; 616231), Rossi et al. (2014) identified a heterozygous missense mutation in the CASQ1 gene (D244G; 114250.0001). Cellular studies showed that the mutation causes the formation of abnormal SR vacuoles containing aggregates of CASQ1 as well as other proteins and results in altered calcium release in skeletal muscle fibers. The phenotype was mild, and some patients were asymptomatic except for increased serum creatine kinase levels.
Di Blasi et al. (2015) identified heterozygosity for the D244G mutation in the CASQ1 gene in 10 patients from 3 unrelated Italian families with VMCQA. The mutation, which was found by a combination of exome sequencing and direct sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect. Cellular transfection studies showed that both wildtype and mutant proteins tended to form aggregates within the cytoplasm, with the aggregates formed by mutated CASQ1 being larger. Electrophoretic studies showed that the mutated protein did not migrate in the same way as the normal protein, suggesting that abnormal protein aggregates likely result from abnormal polymerization of the mutated CASQ1.
Dainese et al. (2009) stated that mice lacking skeletal Casq1 are viable but exhibit reduced levels of releasable Ca(2+) and show altered contractile properties. They found that Casq1 -/- mice exhibited moderately increased spontaneous mortality and susceptibility to heat- and anesthetic-induced sudden death. Exposing Casq1 -/- mice to 2% halothane or heat stress triggered lethal episodes characterized by whole-body contractures, elevated core temperature, and severe rhabdomyolysis. Mortality and all responses were predominantly found in male Casq1 -/- mice and were prevented by prior administration of dantrolene. Male Casq1 -/- muscle exhibited increased contractile sensitivity to temperature and caffeine, temperature-dependent increases in resting Ca(2+), and increased magnitude of depolarization-induced Ca(2+) release. Dainese et al. (2009) observed that responses of Casq1 -/- mice to heat and anesthetics were similar to episodes in humans with malignant hyperthermia (MH; see 145600) and in animal models of MH and environmental heat stroke. They hypothesized that CASQ1 deficiency alters proper control of RYR1 (180901) function.
Paolini et al. (2011) found that mice lacking both Casq1 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 7 members of 4 Italian families with vacuolar myopathy with CASQ1 aggregates (VMCQA; 616231), Rossi et al. (2014) identified a heterozygous c.731A-G transition in the CASQ1 gene, resulting in an asp244-to-gly (D244G) substitution at a highly conserved residue that contributes to form one of the high-affinity calcium-binding sites of the protein. The variant was not found in the dbSBP, 1000 Genomes Project, or Exome Variant Server databases, or in 400 control DNAs, and it segregated with the disorder in all 4 families where segregation analysis was possible. One of the families had previously been reported by Tomelleri et al. (2006). Haplotype analysis suggested a common founder for at least 2 of the families, who originated from northeastern Italy. An unrelated Italian patient with sporadic disease was also found to carry the D244G mutation. Single muscle fibers from 2 patients showed reduced responsiveness of calcium release from the sarcoplasmic reticulum compared to controls. Transfection of the mutation into COS-7 cells showed that the mutation caused impaired polymerization of CASQ1. Expression of the mutant protein in primary rat myoblasts showed that it colocalized with RYR1 (180901) at the junctional regions of the SR, similar to wildtype, but that it formed large intracellular aggregates similar to those observed in patient muscle biopsies.
Di Blasi et al. (2015) identified heterozygosity for the D244G mutation in the CASQ1 gene in 10 patients from 3 unrelated Italian families with VMCQA. The mutation, which was found by a combination of exome sequencing and direct sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect. Cellular transfection studies showed that both wildtype and mutant proteins tended to form aggregates within the cytoplasm, with the aggregates formed by mutated CASQ1 being larger. Electrophoretic studies showed that the mutated protein did not migrate in the same way as the normal protein, suggesting that abnormal protein aggregates likely result from abnormal polymerization of the mutated CASQ1.
Bataille, N., Schmitt, N., Aumercier-Maes, P., Ollivier, B., Lucas-Heron, B., Lestienne, P. Molecular cloning of human calmitine, a mitochondrial calcium binding protein, reveals identity with calsequestrine. Biochem. Biophys. Res. Commun. 203: 1477-1482, 1994. [PubMed: 7945294] [Full Text: https://doi.org/10.1006/bbrc.1994.2351]
Dainese, M., Quarta, M., Lyfenko, A. D., Paolini, C., Canato, M., Reggiani, C., Dirksen, R. T., Protasi, F. Anesthetic- and heat-induced sudden death in calsequestrin-1-knockout mice. FASEB J. 23: 1710-1720, 2009. [PubMed: 19237502] [Full Text: https://doi.org/10.1096/fj.08-121335]
Di Blasi, C., Sansanelli, S., Ruggieri, A., Moriggi, M., Vasso, M., D'Adamo, A. P., Blasevich, F., Zanotti, S., Paolini, C., Protasi, F., Tezzon, F., Gelfi, C., Morandi, L., Pessia, M., Mora, M. A CASQI founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia. J. Med. Genet. 52: 617-626, 2015. [PubMed: 26136523] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102882]
Fujii, J., Willard, H. F., MacLennan, D. H. Characterization and localization to human chromosome 1 of human fast-twitch skeletal muscle calsequestrin gene. Somat. Cell Molec. Genet. 16: 185-189, 1990. [PubMed: 2321095] [Full Text: https://doi.org/10.1007/BF01233048]
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]
Rossi, D., Vezzani, B., Galli, L., Paolini, C., Toniolo, L., Pierantozzi, E., Spinozzi, S., Barone, V., Pegoraro, E., Bello, L., Cenacchi, G., Vattemi, G., Tomelleri, G., Ricci, G., Siciliano, G., Protasi, F., Reggiani, C., Sorrentino, V. A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates. Hum. Mutat. 35: 1163-1170, 2014. [PubMed: 25116801] [Full Text: https://doi.org/10.1002/humu.22631]
Tomelleri, G., Palmucci, L., Tonin, P., Mongini, T., Marini, M., L'Erario, R., Rizzuto, N., Vattemi, G. SERCAI and calsequestrin storage myopathy: a new surplus protein myopathy. Brain 129: 2085-2092, 2006. [PubMed: 16714317] [Full Text: https://doi.org/10.1093/brain/awl128]