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Other entities represented in this entry:
HGNC Approved Gene Symbol: CASP10
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38): 2:201,183,141-201,229,406 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | Autoimmune lymphoproliferative syndrome, type II | 603909 | Autosomal dominant | 3 |
| Gastric cancer, somatic | 613659 | 3 | ||
| Lymphoma, non-Hodgkin, somatic | 605027 | 3 |
Caspase-10 is an aspartate-specific cysteine protease of the ICE/CED3 (see 147678) family. These proteases take part in a cascade of reactions thought to be responsible for the apoptotic changes observed in mammalian cells undergoing programmed cell death (Fernandes-Alnemri et al., 1996).
Fernandes-Alnemri et al. (1996) used degenerate PCR to identify CASP10, a novel member of the ICE/CED3 protease family. They subsequently cloned the cDNA, which they termed MCH4, from a human Jurkat T-cell cDNA library. Sequence analysis revealed that MCH4 encodes a 479-amino acid polypeptide. They found that MCH4 is most closely related to MCH5 (CASP8; 601763) and that MCH4 and MCH5 contain the active site pentapeptide QACQG instead of the QACRG present in all other known members of the family. Furthermore, the authors found that the sequences of MCH4 and MCH5 contain Fas-associating protein with death domain (FADD; 602457)-like domains, suggesting possible interaction with FADD. Northern blot analysis showed that MCH4 was expressed as a 4-kb message in most human tissues examined.
By searching an EST database for clones containing the conserved GSW sequences found in the small catalytic subunit of caspases, Vincenz and Dixit (1997) identified a cDNA encoding a splice variant of CASP10, CASP10B, which they called FLICE2. Sequence analysis predicted that the deduced 521-amino acid FLICE2 protein contains a 50-amino acid insert in the C terminus of the prodomain and a 48-amino acid sequence distinct from CASP10 at the C terminus. FLICE2 also contains 2 death effector domains (DEDs). Northern blot analysis detected a 4.4-kb FLICE2 transcript particularly in tissues enriched in lymphoid cells and in the K562 chronic myelogenous leukemia cell line.
Fernandes-Alnemri et al. (1996) stated that MCH4, like other members of the ICE/CED3 family, forms an active protease only after cleavage of its proenzyme into 2 subunits which dimerize to form the active enzyme. They found that the mature enzyme cleaves both CPP32 (CASP3; 600636) and MCH3 (601761) proenzymes into their mature forms.
Functional analysis by Vincenz and Dixit (1997) showed that FLICE2 cleaves poly(ADP-ribose) polymerase (PARP; 173870) to its 85-kD apoptotic form, binds FADD through the DEDs of each molecule, and binds to the CD95 (TNFRSF6, or FAS; 134637) and TNFR1 (191190) death receptors. The binding of CD95 and TNFR1 by FLICE2 is enhanced in the presence of FADD. Overexpression of FLICE2, but not overexpression of an active-site mutant, induced apoptosis.
Wang et al. (2001) showed that caspase-10 can function independently of caspase-8 (CASP8; 601763) in initiating FAS- and tumor necrosis factor-related apoptosis-inducing ligand-receptor-mediated apoptosis. Moreover, FAS crosslinking in primary human T cells leads to the recruitment and activation of caspase-10. They showed that the death-effector domains of caspases 8 and 10 interact with the death-effector domain of FADD. Nonetheless, they found that caspases 8 and 10 may have different apoptosis substrates and therefore potentially distinct roles in death receptor signaling or other cellular processes.
Lee et al. (2007) showed that intrinsic apoptosis in human cells that was induced by the chemotherapeutic agent etoposide or the antibiotic staurosporine, but not by FAS ligand (TNFSF6; 134638) or TRAIL (TNFSF10; 603598), caused translocation of AK2 (103020) from mitochondria to the cytoplasm, followed by formation of a complex between AK2, FADD, and CASP10. Yeast 2-hybrid analysis, protein pull-down assays, and immunoprecipitation analysis showed that the N- and C-terminal domains of AK2, which include nucleoside- and substrate-binding domains, respectively, bound the C-terminal death domain of FADD. AK2 binding promoted association of CASP10 with FADD, and addition of purified AK2 protein to cell extracts induced activation of CASP10 via FADD, leading to subsequent activation of CASP9 (602234) and CASP3. Apoptosis through the AK2 complex did not correlate with the adenylate kinase activity of AK2, did not require CASP8-mediated apoptotic responses, and did not involve mitochondrial cytochrome c release. Immunodepletion or knockdown of AK2, FADD, or CASP10 abrogated etoposide-induced apoptosis, and AK2 complexes were not observed in several etoposide-resistant human tumor cell lines that were deficient in expression of FADD, CASP10, or CASP3. In contrast to the findings in human cells, etoposide-induced apoptosis was observed in mouse embryonic fibroblasts that lacked Fadd expression. Since mice also lack Casp10, Lee et al. (2007) concluded that mice lack an apoptotic pathway comparable to the AK2-FADD-CASP10 pathway in humans.
Hadano et al. (2001) determined that the CASP10 gene contains 11 exons and spans about 48 kb. It is transcribed in the centromere-to-telomere direction.
Fernandes-Alnemri et al. (1996) mapped the MCH4 gene to 2q33-q34 by FISH. Hadano et al. (2001) determined that the CFLAR (603599), CASP10, and CASP8 genes are tandemly located within 200 kb.
Autoimmune Lymphoproliferative Syndrome type IIA
In an African American girl with type IIA autoimmune lymphoproliferative syndrome (ALPS2A; 603909) characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects, Wang et al. (1999) identified a heterozygous mutation in the CASP10 gene (L285F; 601762.0001). The mutation resulted in decreased caspase activity and interfered with death receptor-induced apoptosis, particularly that stimulated by Fas ligand (134638) and TRAIL (603598). These results provided evidence that inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS2. A second patient, of Ashkenazi Jewish descent, was reported to have a homozygous substitution in the CASP10 gene (V410I), which was later determined to be a polymorphism with apoptotic activity similar to the wildtype CASP10 protein (Gronbaek et al., 2000; Zhu et al., 2006). In addition, the Ashkenazi Jewish patient was found to have a mutation in the TNFRSF1A gene (191190), which is mutated in the TNF receptor-associated periodic syndrome (TRAPS; 142680) (Zhu et al., 2006). Zhu et al. (2006) presented association data suggesting that the V410I substitution may offer some protection from severe disease in patients with ALPS1A (601859) who have mutations in the TNFRSF6 gene (134637).
In 2 sisters and an unrelated boy with APLS2A, Zhu et al. (2006) identified a heterozygous pathogenic mutation in the CASP10 gene (I406L; 601762.0007).
Cancer
To explore the possibility that mutation in the CASP10 gene might be involved in the development of non-Hodgkin lymphoma (NHL; 605027), Shin et al. (2002) analyzed the entire coding region and all splice sites of the CASP10 gene for the detection of somatic mutations in 117 human NHLs. Seventeen NHLs (14.5%) had CASP10 mutations, of which 3 were identified in the coding regions of the prodomain, 11 in the p17 large protease subunit, and 3 in the p12 small protease subunit. There were 2 frameshift mutations and 1 nonsense mutation; the remaining 14 were missense mutations. Shin et al. (2002) expressed the tumor-derived CASP10 mutants in 293 cells and found that apoptosis was suppressed. These data suggested that the inactivating mutations of the CASP10 gene may lead to the loss of its apoptotic function and contribute to the pathogenesis of some human NHLs.
Park et al. (2002) analyzed the genetic alterations of the entire coding region and all splice sites of the CASP8 and CASP10 genes in 99 gastric cancers by PCR-SSCP and sequencing. Of the 99 gastric cancers, 3 had CASP10 mutations, whereas no mutations were detected in CASP8. In vitro expression studies showed that the met147-to-thr (M147T; 601762.0006) and gln257-to-ter (Q257X; 601762.0004) mutants severely impaired CASP10-mediated apoptosis. Park et al. (2002) suggested that somatic alterations of the CASP10 gene may contribute to pathogenesis in a subset of gastric cancers through loss of apoptotic function.
In an African American patient with ALPS2A (603909), Wang et al. (1999) identified a heterozygous 724C-T transition in the CASP10 gene, resulting in a leu242-to-phe (L242F) substitution (L285F in the longer CASP10 isoform). The proband's mother, who exhibited high levels of autoantibodies to nuclear antigens and defective lymphocyte apoptosis, also had the mutation. The proband's unaffected father and 2 sisters did not have the mutation. The mutation was not found in 200 normal chromosomes or in any patient with ALPS type I (601859).
In a peripheral T-cell lymphoma (605027), Shin et al. (2002) observed a 1241C-T transition in exon 9 of the CASP10 gene, resulting in an ala414-to-val (A414V) amino acid change.
In a diffuse large B-cell lymphoma (605027), Shin et al. (2002) observed a 769C-T transition in exon 7 of the CASP10 gene, converting gln257 to ter (Q257X).
Park et al. (2002) identified a somatic Q257X mutation in gastric cancer tissue. In vitro expression studies showed that Q257X mutation severely impaired caspase-10-mediated apoptosis.
In a patient with MALT (mucosa-associated lymphoid tissue) lymphoma (605027), Shin et al. (2002) found a 1-bp insertion, an adenine after nucleotide 1042, resulting in frameshift and termination at amino acid 367.
Park et al. (2002) identified 3 somatic mutations in the CASP10 gene in gastric cancers (137215): met147 to thr (M147T), and the previously described gln257 to ter (Q257X; 601762.0004). By in vitro expression studies, they showed that the M147T and Q257X mutations severely impaired caspase-10-mediated apoptosis.
This variant, formerly titled AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIA, has been reclassified based on the report of Lek et al. (2016).
In a 7-year-old boy with ALPS2A (603909), Zhu et al. (2006) identified a heterozygous 1400A-T transversion in exon 9 of the CASP10 gene, resulting in an ile406-to-leu (I406L) substitution near the active site of the protein. Neither parent had a history suggestive of ALPS, but his father, an adult-onset diabetic, also carried the mutation. The I406L mutation was also identified in 2 sisters of mixed Jamaican and Guyanese ancestry who had early-onset ALPS2A. Their mother and a third sister were mutation carriers and asymptomatic at the time of evaluation, but showed defective T cell apoptosis in vitro, increased numbers of double-negative T cells, and positive direct antiglobulin IgG tests and antithyroid antibodies. In vitro functional expression studies showed that the I406L mutant protein had defective apoptosis and exerted a dominant-negative effect when cotransfected with the wildtype protein. The I406L substitution was not identified in 576 controls.
Lek et al. (2016) noted that the I406L variant has a high allele frequency (0.0151) in the South Asian population in the ExAC database, suggesting that it is not pathogenic.
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Zhu, S., Hsu, A. P., Vacek, M. M., Zheng, L., Schaffer, A. A., Dale, J. K., Davis, J., Fischer, R. E., Straus, S. E., Boruchov, D., Saulsbury, F. T., Lenardo, M. J., Puck, J. M. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum. Genet. 119: 284-294, 2006. [PubMed: 16446975] [Full Text: https://doi.org/10.1007/s00439-006-0138-9]