Alternative titles; symbols
HGNC Approved Gene Symbol: CAPN1
SNOMEDCT: 1172631001;
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:65,181,373-65,212,006 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Spastic paraplegia 76, autosomal recessive | 616907 | Autosomal recessive | 3 |
Calpain (calcium-dependent protease; EC 3.4.22.17) is an intracellular protease that requires calcium for its catalytic activity. Two isozymes, calpain I (mu-calpain) and calpain II (m-calpain), with different calcium requirements, have been identified. Both are heterodimers composed of L (large, catalytic, 80 kD) and S (small, regulatory, 30 kD) subunits. The isozymes share an identical S subunit (CAPNS1; 114170), with the differences arising from the L subunits, L1 (CAPN1) and L2 (CAPN2; 114230) (summary by Ohno et al., 1990).
Using a fragment of the large subunit of rabbit mu-Canp to screen a human skeletal muscle cDNA library, followed by screening a human spleen cDNA library, Aoki et al. (1986) cloned CAPN1, which they called mu-CANP large subunit. The deduced 714-amino acid protein has a calculated molecular mass of 81.9 kD. Like the large subunit of chicken Canp, human CAPN1 has a 4-domain structure, including 2 thiol protease domains and a calmodulin (see 114180)-like Ca(2+)-binding domain. Domain II harbors the active site residues cys115 and his272, and domain IV is made up of 4 consecutive EF-hand motifs that are predicted to bind Ca(2+). Northern blot analysis of human spleen RNA detected a 3.5-kb CAPN1 transcript.
Using cDNA clones as probes, Ohno et al. (1989, 1990) mapped the CANPL1 and CANPL2 genes as well as the CANPS gene and a gene for another protein, L3 (CAPN3; 114240), that is homologous to the other 2 L subunits. They used a combination of spot-blot hybridization with sorted chromosomes and Southern hybridization with human-mouse cell hybrid DNAs. In this way they were able to assign CANPL1 to chromosome 11, CANPL2 to chromosome 1, CANPL3 to chromosome 15, and CANPS to chromosome 19.
Courseaux et al. (1996) used a combination of methods to refine maps of an approximately 5-Mb region of 11q13. They mapped the CAPN1 gene within this region, telomeric to the FAU gene (134690) and centromeric to the MLK3 (MAP3K11; 600050) and RELA (164014) genes.
By quantitative RT-PCR, Ueyama et al. (1998) found that expression of calpain-1 and calpain-2 mRNA was significantly increased in muscle biopsy samples derived from 5 men with progressive muscular dystrophy (e.g., DMD; 310200) and 2 men and 3 women with amyotrophic lateral sclerosis (ALS; 105400) compared with controls.
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.
In affected members of 3 unrelated families with autosomal recessive spastic paraplegia-76 (SPG76; 616907), Gan-Or et al. (2016) identified homozygous or compound heterozygous mutations in the CAPN1 gene (114220.0001-114220.0004). The mutations were found by whole-exome sequencing and segregated with the disorder in the families. One of the mutations was a missense mutation, whereas the others were nonsense, frameshift, or splice site mutations. Functional studies of the variants and studies of patient cells were not performed, but knockdown of the Capn1 gene in animal models resulted in disruption of neuronal patterning and neurodegeneration (see ANIMAL MODEL).
Using a genomewide association study in 16 Parson Russell terriers (PRTs) with spinocerebellar ataxia (SCA; see 164400) and 16 controls, followed by target-enriched massively parallel sequencing, Forman et al. (2013) identified a highly associated nonsynonymous SNP in the Capn1 gene in affected PRTs. The 344G-A SNP resulted in a cys115-to-tyr (C115T) substitution that affected the highly conserved catalytic cysteine. Genotyping 27 additional PRTs with SCA and 200 controls identified 23 affected PRTs that were homozygous for the SCA-associated SNP, whereas no controls were homozygous for the SNP. Among 5 Jack Russell terriers with SCA, 3 were homozygous wildtype, 1 was heterozygous for the SCA-associated SNP, and 1 was homozygous for the SCA-associated SNP. Forman et al. (2013) hypothesized that mutations in the CAPN1 gene may cause SCA in humans.
Gan-Or et al. (2016) found that RNAi knockdown of the Capn1 gene in C. elegans resulted in neurodegeneration of GABAergic motor neurons and an age-dependent paralysis phenotype. Loss of Capn1 in Drosophila led to locomotor defects, axonal abnormalities, and age-dependent negative geotaxis. The axons appeared to have larger diameters and increased levels of acetylated tubulin. Morpholino knockdown of capn1a in Zebrafish resulted in disruption of brain development, particularly of branchiomotor neuron migration and positioning, as well as disorganization of the microtubule network with some regions showing abnormal accumulation and others showing depletion of axonal acetylated tubulin. These animal models supported a neuroprotective role of Capn1.
In 3 affected members of a consanguineous Moroccan family (family A) with autosomal recessive spastic paraplegia-76 (SPG76; 616907), Gan-Or et al. (2016) identified a homozygous c.884G-C transversion (c.884G-C, NM_005186) in exon 8 of the CAPN1 gene, resulting in an arg295-to-pro (R295P) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house dataset of over 1,600 exomes. The substitution is located next to an active site in position 296, which is a critical calcium-binding site at the end of a beta-strand. Homozygosity mapping was consistent with the results. Functional studies of the variant and studies of patient cells were not performed.
In 4 sibs, born of consanguineous Moroccan parents (family B), with autosomal recessive spastic paraplegia-76 (SPG76; 616907), Gan-Or et al. (2016) identified a homozygous c.1579C-T transition (c.1579C-T, NM_005186) in exon 14 of the CAPN1 gene, resulting in a gln527-to-ter (Q527X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house dataset of over 1,600 exomes. Homozygosity mapping was consistent with the results. Functional studies of the variant and studies of patient cells were not performed.
In 2 affected members of a North American family (family C) with recessive spastic paraplegia-76 (SPG76; 616907), Gan-Or et al. (2016) identified compound heterozygous mutations in the CAPN1 gene: a 1-bp deletion in exon 4 (c.406delC, NM_005186), resulting in a frameshift and premature termination (Pro136ArgfsTer40), and a G-to-A transition (c.1605+5G-A; 114220.0004), resulting in a splice site mutation and the skipping of exon 14. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the 1000 Genomes Project, Exome Sequencing Project, or in an in-house dataset of over 1,600 exomes. The splice site variant was found at low frequency (0.0001) in the ExAC browser. Functional studies of the variant and studies of patient cells were not performed.
For discussion of the c.1605+5G-A transition in the CAPN1 gene, resulting in a splice site mutation and the skipping of exon 14, that was found in compound heterozygous state in affected members of a family with spastic paraplegia-76 (SPG76; 616907) by Gan-Or et al. (2016), see 114220.0003.
Aoki, K., Imajoh, S., Ohno, S., Emori, Y., Koike, M., Kosaki, G., Suzuki, K. Complete amino acid sequence of the large subunit of the low-Ca(2+)-requiring form of human Ca(2+)-activated neutral protease (mu-CANP) deduced from its cDNA sequence. FEBS Lett. 205: 313-317, 1986. [PubMed: 3017764] [Full Text: https://doi.org/10.1016/0014-5793(86)80919-x]
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]
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
Forman, O. P., De Risio, L., Mellersh, C. S. Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed. PLoS One 8: e64627, 2013. Note: Electronic Article. [PubMed: 23741357] [Full Text: https://doi.org/10.1371/journal.pone.0064627]
Gan-Or, Z., Bouslam, N., Birouk, N., Lissouba, A., Chambers, D. B., Verlepe, J., Androschuk, A., Laurent, S. B., Rochesfort, D., Spiegelman, D., Dionne-Laporte, A., Szuto, A., and 15 others. Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia. Am. J. Hum. Genet. 98: 1038-1046, 2016. Note: Erratum: Am. J. Hum. Genet. 98: 1271 only, 2016. [PubMed: 27153400] [Full Text: https://doi.org/10.1016/j.ajhg.2016.04.002]
Ohno, S., Minoshima, S., Kudoh, J., Fukuyama, R., Ohmi-Imajoh, S., Suzuki, K., Shimizu, Y., Shimizu, N. Four genes for the calpain family locate on four distinct human chromosomes. (Abstract) Cytogenet. Cell Genet. 51: 1054-1055, 1989.
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]
Ueyama, H., Kumamoto, T., Fujimoto, S., Murakami, T., Tsuda, T. Expression of three calpain isoform genes in human skeletal muscles. J. Neurol. Sci. 155: 163-169, 1998. [PubMed: 9562261] [Full Text: https://doi.org/10.1016/s0022-510x(97)00309-2]