Alternative titles; symbols
HGNC Approved Gene Symbol: CAPNS1
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:36,140,066-36,150,353 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.12 | Pulmonary hypertension, primary, 6 | 620777 | Autosomal recessive | 3 |
Calcium-dependent cysteine proteinases, or calpains (EC 3.4.22.17), are widely distributed in mammalian cells. There are 2 distinct molecular forms, calpains I and II, which differ in the quantity of calcium required. Both calpains I and II are heterodimeric; each is composed of 1 heavy (about 80 kD), CAPN1 (114220) and CAPN2 (114230), respectively, and 1 shared light (about 30 kD) subunit, CAPNS1. The heavy subunit has a catalytic function, and the light subunit is regulatory.
Ohno et al. (1986) gave the nucleotide sequence for a nearly full-length cDNA coding for the small subunit of human calcium-dependent protease. A human spleen cDNA library was the source. The human protein has 268 amino acids.
By a combination of spot blot hybridization with sorted chromosomes and of Southern hybridization with human-mouse cell hybrid DNAs, using in each case a cDNA probe, Ohno et al. (1990) assigned the CANPS gene to chromosome 19.
Using cell biologic, pharmacologic, and genetic methods, Chandramohanadas et al. (2009) found that the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii, the causative agents of malaria and toxoplasmosis, respectively, used host cell calpains to facilitate parasite egress. Immunodepletion and inhibition experiments showed that calpain-1 was required for escape of P. falciparum from human erythrocytes. Similarly, elimination of both calpain-1 and calpain-2 via small interfering RNA against the common regulatory subunit CAPNS1 in human osteosarcoma cells or deletion of Capns1 in mouse embryonic fibroblasts blocked egress of T. gondii. Chandramohanadas et al. (2009) concluded that P. falciparum and T. gondii both exploit host cell calpains to facilitate escape from intracellular parasitophorous vacuoles and/or the host plasma membrane, a process required for parasite proliferation.
Crystal Structure
Blanchard et al. (1997) reported the crystal structure of the Ca(2+)-binding domain (domain VI) of rat Capns1 at 2.3-angstrom resolution, both with and without bound Ca(2+). Monomers of domain VI formed dimers with or without Ca(2+). The domain VI monomer was compact, predominantly alpha helical, and incorporated 5 EF-hand supersecondary structural elements. Only EF1, EF2, and EF3 were able to bind Ca(2+) at physiologic Ca(2+) concentrations, and EF1 showed a novel Ca(2+) coordination pattern.
In 2 Tunisian sisters and a Dutch man, who all died with severe primary pulmonary arterial hypertension (PPH6; 620777), Postma et al. (2023) identified homozygosity for splice site mutations in the CAPNS1 gene (114170.0001 and 114170.0002, respectively) that segregated fully with disease in both families and were not found in the gnomAD database. Functional analysis indicated that the aberrant splicing resulted in complete absence of the CAPNS1 protein in affected individuals.
Using targeted disruption of the mouse Capn4 gene and casein zymography analysis, Arthur et al. (2000) demonstrated that wildtype and heterozygote embryonic stem cell lysates maintained mu- and m-calpain (i.e., calpain I and II) activities, whereas mutant homozygote embryonic stem cell lysates did not. Immunoblot analysis showed that the m-calpain large subunit was lost in Capn4 -/- cells. Growth of fibroblasts from day 9.5 Capn4 -/- embryos was indistinguishable from those of wildtype and heterozygous mice. At day 10.5, Capn4 -/- mice had a normal cardiovascular system except for apparent defects in the development of heart chambers and the vessels leading to and from the heart. After day 11.5, the accumulation of nucleated erythroid cells correlated with the death of all Capn4 -/- embryos. Although unable to determine a physiologic function for calpain, Arthur et al. (2000) concluded that calpain is essential for life.
In 2 Tunisian sisters (P2 and P3, family A), who both died at age 29 months with primary pulmonary hypertension (PPH6; 620777), Postma et al. (2023) identified homozygosity for a splice site mutation (c.721+1G-A, NM_001749.4) in intron 8 of the CAPNS1 gene. Their unaffected first-cousin parents and an unaffected sister were heterozygous for the mutation, which was not found in the gnomAD database; DNA was unavailable from an older sister (P1) who died at 17 months of age with a diagnosis of hypertrophic cardiomyopathy. RNA expression analysis showed that the mutation caused in-frame skipping of exon 8, resulting in a CAPNS1 protein missing 39 amino acids within the fourth and fifth EF-hand domains. A shorter CAPNS1 protein was not detected in cells from the heterozygous parents and sister; in vitro experiments demonstrated that the aberrant shorter protein is degraded by the proteasome. This family had previously been reported by Navarini et al. (2011), who had excluded mutation in the BMPR2 gene (600799) in the proband (P2).
In a Dutch man (P5, family B) who died at age 42 years with primary pulmonary hypertension (PPH6; 620777), Postma et al. (2023) identified homozygosity for a splice site mutation (c.210-2A-G, NM_001749.4) in intron 1 of the CAPNS1 gene. His unaffected first-cousin parents were heterozygous for the mutation, which was not found in his unaffected sister or in the gnomAD database; DNA was unavailable from an older brother (P4) who had died at age 5 years with cardiopulmonary disease and suspected pulmonary hypertension. RNA analysis identified 2 aberrant CAPNS1 transcripts in patient P5, one with loss of exon 2 and the other using a cryptic splice site within exon 2; both were predicted to cause a frameshift resulting in a premature termination codon (Glu71ProfsTer40 and Ser70ArgfsTer51, respectively). Western blot analysis confirmed complete absence of CAPNS1 protein in patient P5. The authors noted that P5 was recruited as part of another project, involving large-scale sequencing of 13,037 individuals, including 1,150 with pulmonary arterial hypertension. Patient P5 was the only individual from that cohort with biallelic likely pathogenic variants in the CAPNS1 gene, suggesting that CAPNS1 represents a relatively rare monogenic cause of primary pulmonary hypertension.
Arthur, J. S. C., Elce, J. S., Hegadorn, C., Williams, K., Greer, P. A. Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division. Molec. Cell. Biol. 20: 4474-4481, 2000. [PubMed: 10825211] [Full Text: https://doi.org/10.1128/MCB.20.12.4474-4481.2000]
Blanchard, H., Grochulski, P., Li, Y., Arthur, J. S. C., Davies, P. L., Elce, J. S., Cygler, M. Structure of a calpain Ca(2+)-binding domain reveals a novel EF-hand and Ca(2+)-induced conformational changes. Nature Struct. Biol. 4: 532-538, 1997. [PubMed: 9228945] [Full Text: https://doi.org/10.1038/nsb0797-532]
Chandramohanadas, R., Davis, P. H., Beiting, D. P., Harbut, M. B., Darling, C., Velmourougane, G., Lee, M. Y., Greer, P. A., Roos, D. S., Greenbaum, D. C. Apicomplexan parasites co-opt host calpains to facilitate their escape from infected cells. Science 324: 794-797, 2009. [PubMed: 19342550] [Full Text: https://doi.org/10.1126/science.1171085]
Navarini, S., Bucher, B., Pavlovic, M., Pfammatter, J. P., Casaulta, C., Brasch, F., Griese, M., Regamey, N. Pulmonary hypertension presenting with apnea, cyanosis, and failure to thrive in a young child. Chest 140: 1086-1089, 2011. [PubMed: 21972389] [Full Text: https://doi.org/10.1378/chest.10-2607]
Ohno, S., Emori, Y., Suzuki, K. Nucleotide sequence of a cDNA coding for the small subunit of human calcium-dependent protease. Nucleic Acids Res. 14: 5559 only, 1986. [PubMed: 3016651]
Ohno, S., Minoshima, S., Kudoh, J., Fukuyama, R., Shimizu, Y., Ohmi-Imajoh, S., Shimizu, N., Suzuki, K. Four genes for the calpain family locate on four distinct human chromosomes. Cytogenet. Cell Genet. 53: 225-229, 1990. [PubMed: 2209092] [Full Text: https://doi.org/10.1159/000132937]
Postma, A. V., Rapp, C. K., Knoflach, K., Volk, A. E., Lemke, J. R., Ackermann, M., Regamey, N., Latzin, P., Celant, L., Jansen, S. M. A., Bogaard, H. J., Ilgun, A., Alders, M., van Spaendonck-Zwarts, K. Y., Jonigk, D., Klein, C., Graf, S., Kubisch, C., Houweling, A. C., Griese, M. Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension. Genet. Med. Open 1: 100811, 2023. [PubMed: 38230350] [Full Text: https://doi.org/10.1016/j.gimo.2023.100811]
Sakihama, T., Kakidani, H., Zenita, K., Yumoto, N., Kikuchi, T., Sasaki, T., Kannagi, R., Nakanishi, S., Ohmori, M., Takio, K., Titani, K., Murachi, T. A putative Ca(2+)-binding protein: structure of the light subunit of porcine calpain elucidated by molecular cloning and protein sequence analysis. Proc. Nat. Acad. Sci. 82: 6075-6079, 1985. [PubMed: 2994060] [Full Text: https://doi.org/10.1073/pnas.82.18.6075]