Alternative titles; symbols
HGNC Approved Gene Symbol: CASP7
Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38): 10:113,679,194-113,730,909 (from NCBI)
Programmed cell death (apoptosis) is associated with the hierarchical activation of a number of cysteine proteinases with cleavage preference after asparagine residues, comprising the caspase family C14 of clan CD (Barrett and Rawlings, 2001). Based on their position within this proteolytic cascade, caspases are subdivided into initiator caspases, which include caspase-8 (601763) and caspase-9 (602234), and executioner caspases, which include caspase-3 (600636, also called CPP32), caspase-6 (601532, also called MCH2), and caspase-7, as well as a third group of caspases involved in cytokine activation, namely, caspase-1 (147678, also called ICE), caspase-4 (602664), and caspase-5 (602665). In apoptosis, the upstream caspases triggered by cofactor-mediated transactivation activate the downstream executioner caspases by limited proteolysis. These executioners, in turn, cleave distinct intracellular proteins involved in promoting the apoptotic phenotype.
Fernandes-Alnemri et al. (1995) used the sequence of a human EST clone to clone CASP7, which they called MCH3, from a human Jurkat T-cell cDNA library. One resultant clone type, MCH3-alpha, encodes a 303-amino acid polypeptide with a predicted molecular mass of approximately 34 kD. They also obtained a second, presumably alternatively spliced, cDNA type, named MCH3-beta, which contains a deletion and insertion within the sequence and a much longer 5-prime untranslated region. The insertion in the MCH3-beta sequence produces a frame shift which results in a shorter, 253-amino acid, approximately 28-kD polypeptide lacking the QACRG pentapeptide, believed to be the cysteine protease active site of all members of the ICE/CED-3 family. Fernandes-Alnemri et al. (1995) suggested that MCH3-beta may act as a negative regulator of apoptosis by acting as a dominant inhibitor of the activity of MCH3-alpha. Sequence analysis revealed that the MCH3-alpha amino acid sequence had the highest homology to CPP32 (53% identity) and less than 37% identity with all other family members. Northern blot analysis of MCH3 by Fernandes-Alnemri et al. (1995) revealed a major 2.4-kb transcript detectable in all tissues examined, with the lowest level of expression being in the brain.
By microarray analysis, Jun et al. (2001) demonstrated expression of the CASP7 gene in human donor corneas.
Fernandes-Alnemri et al. (1995) found that active MCH3-alpha protein is made by the cleavage of pro-MCH3-alpha into 2 subunits, p20 and p12. Active CPP32 is similarly made by cleavage of its precursor, pro-CPP32, into 2 subunits. They found that CPP32 could cleave pro-MCH3-alpha into its subunits, but that MCH3-alpha could not cleave pro-CPP32. The authors further demonstrated that MCH4 (601762) can cleave pro-MCH3 into its 2 subunits (Fernandes-Alnemri et al., 1996). Expression of MCH3-alpha/CPP32 heterodimers in Sf9 cells induced apoptosis. They also found that MCH3 cleaves poly(ADP-ribose) polymerase (PARP) with similar kinetics to that of CPP32. Thus Fernandes-Alnemri et al. (1995) concluded that the cleavage of PARP during apoptosis cannot solely be attributed to CPP32 but could also be an activity of its closely related homolog, MCH3-alpha.
Riedl et al. (2001) crystallized the C285A variant of human procaspase-7 and solved its crystal structure at 2.9 angstrom. Analysis of this executioner zymogen structure and its comparison with the structures of active caspase-7 unveiled the structural basis of the procaspase inactivity and suggested the conformational changes leading to procaspase activation.
Tiso et al. (1996) used radiation hybrid mapping to localize the CASP7 gene to human chromosome 10q25.1-q25.2. They reported that each of the 4 CASP family genes mapped colocalizes with an autosomal dominant malformative disease. They suggested Crouzon craniofacial dysostosis (123500) as a candidate genetic disease at the 10q25-q26 locus.
Burguillos et al. (2011) showed that the orderly activation of caspase-8 (601763) and caspase-3 (600636)/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C-delta (PRKCD; 176977)-dependent pathway. Burguillos et al. (2011) found that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently, reduced neurotoxicity. The authors observed that these caspases are activated in microglia in the ventral mesencephalon of Parkinson disease (168600) and the frontal cortex of individuals with Alzheimer disease (104300). Burguillos et al. (2011) concluded that caspase-8 and caspase-3/7 are involved in regulating microglia activation, and suggested that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
Associations Pending Confirmation
---Cataract, Age-Related
Heyne et al. (2023) analyzed data from the nationwide electronic health records of 176,899 Finnish individuals and identified a significant association between age-related cataract (see 609026) and biallelic variation in the CASP7 gene. Homozygous carriers of a T-C transition at chr10:113725526 (GRCh38) showed an earlier age at diagnosis than heterozygous carriers or wildtype carriers, with cataract present in 50% of homozygotes before the age of 63 years compared to only 3.4% or 3.1% in the heterozygotes or wildtype individuals. The authors stated that this appeared to be the first mendelian gene associated with adult-onset cataract.
---Cancer
Soung et al. (2003) detected somatic CASP7 mutations in 2 of 98 colon carcinomas (2%), 1 of 50 esophageal carcinomas (2%), and 1 of 33 head/neck carcinomas (3%). Expression of the tumor-derived CASP7 mutants in 293T cells showed that apoptosis was reduced. Soung et al. (2003) suggested that inactivating mutations of CASP7 lead to loss of its apoptotic function and contribute to the pathogenesis of some human solid cancers.
Lakhani et al. (2006) generated Casp7-null mice, which were born in ratios consistent with mendelian inheritance. They had normal appearance, organ morphology, and lymphoid development. When Casp7-null mouse embryonic fibroblasts (MEFs) were treated with inducers of apoptosis, they exhibited a slight survival advantage as compared with wildtype MEFs. Apoptosis caused by a range of insults in other Casp7-null cells proceeded normally. Mice doubly deficient for Casp3 and Casp7 died immediately after birth with defects in cardiac development. Fibroblasts lacking both enzymes were highly resistant to both mitochondrial and death receptor-mediated apoptosis, displayed preservation of mitochondrial membrane potential, and had defective nuclear translocation of apoptosis-inducing factor (AIF; 300169). Furthermore, the early apoptotic events of Bax (600040) translocation and cytochrome c (123970) release were also delayed. Lakhani et al. (2006) concluded that caspases 3 and 7 are critical mediators of mitochondrial events of apoptosis.
Barrett, A. J., Rawlings, N. D. Evolutionary lines of cysteine peptidases. Biol. Chem. 382: 727-733, 2001. [PubMed: 11517925] [Full Text: https://doi.org/10.1515/BC.2001.088]
Burguillos, M. A., Deierborg, T., Kavanagh, E., Persson, A., Hajji, N., Garcia-Quintanilla, A., Cano, J., Brundin, P., Englund, E., Venero, J. L., Joseph, B. Caspase signalling controls microglia activation and neurotoxicity. Nature 472: 319-324, 2011. [PubMed: 21389984] [Full Text: https://doi.org/10.1038/nature09788]
Fernandes-Alnemri, T., Armstrong, R. C., Krebs, J., Srinivasula, S. M., Wang, L., Bullrich, F., Fritz, L. C., Trapani, J. A., Tomaselli, K. J., Litwack, G., Alnemri, E. S. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc. Nat. Acad. Sci. 93: 7464-7469, 1996. [PubMed: 8755496] [Full Text: https://doi.org/10.1073/pnas.93.15.7464]
Fernandes-Alnemri, T., Takahashi, A., Armstrong, R., Krebs, J., Fritz, L., Tomaselli, K. J., Wang, L., Yu, Z., Croce, C. M., Salveson, G., Earnshaw, W. C., Litwack, G., Alnemri, E. S. Mch3, a novel human apoptotic cysteine protease highly related to CPP32. Cancer Res. 55: 6045-6052, 1995. [PubMed: 8521391]
Heyne, H. O., Karjalainen, J., Karczewski, K. J., Lemmela, S. M., Zhou, W., FinnGen, Havulinna, A. S., Kurki, M., Rehm, H. L., Palotie, A., Daly, M. J. Mono- and biallelic variant effects on disease at biobank scale. Nature 613: 519-525, 2023. [PubMed: 36653560] [Full Text: https://doi.org/10.1038/s41586-022-05420-7]
Jun, A. S., Liu, S. H., Koo, E. H., Do, D. V., Stark, W. J., Gottsch, J. D. Microarray analysis of gene expression in human donor corneas. Arch. Ophthal. 119: 1629-1634, 2001. [PubMed: 11709013] [Full Text: https://doi.org/10.1001/archopht.119.11.1629]
Lakhani, S. A., Masud, A., Kuida, K., Porter, G. A., Jr., Booth, C. J., Mehal, W. Z., Inayat, I., Flavell, R. A. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311: 847-851, 2006. [PubMed: 16469926] [Full Text: https://doi.org/10.1126/science.1115035]
Riedl, S. J., Fuentes-Prior, P., Renatus, M., Kairies, N., Krapp, S., Huber, R., Salvesen, G. S., Bode, W. Structural basis for the activation of human procaspase-7. Proc. Nat. Acad. Sci. 98: 14790-14795, 2001. [PubMed: 11752425] [Full Text: https://doi.org/10.1073/pnas.221580098]
Soung, Y. H., Lee, J. W., Kim, H. S., Park, W. S., Kim, S. Y., Lee, J. H., Park, J. Y., Cho, Y. G., Kim, C. J., Park, Y. G., Nam, S. W., Jeong, S. W., Kim, S. H., Lee, J. Y., Yoo, N. J., Lee, S. H. Inactivating mutations of CASPASE-7 gene in human cancers. Oncogene 22: 8048-8052, 2003. [PubMed: 12970753] [Full Text: https://doi.org/10.1038/sj.onc.1206727]
Tiso, N., Pallavicini, A., Muraro, T., Zimbello, R., Apolloni, E., Valle, G., Lanfranchi, G., Danieli, G. A. Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis. Biochem. Biophys. Res. Commun. 225: 983-989, 1996. [PubMed: 8780721] [Full Text: https://doi.org/10.1006/bbrc.1996.1282]