Alt. symbols: MCH4 | FLICE-2

Approved name: caspase 10
Alt. names: caspase 10, apoptosis-related cysteine protease, caspase 10, apoptosis-related cysteine peptidase | FAS-associated death domain protein interleukin-1B-converting enzyme 2

Location: 2q33.1: 201182872 - 201229428 (+)
Gene type: protein_coding, 15 transcripts.

Scores: LoFtool: 0.454000 | pLI: 0.00000000 | LOEUF: 1.287

HGNC: 1500

NCBI: 843, RefSeq: NG_007265.1

Ensembl: ENSG00000003400.16

LRG_33 | Status: public

OMIM: 601762

Expression | ProteinAtlas

The CASP10 gene comprises 11 exons and encodes caspase-10, a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved Asp residues to produce two subunits, large and small, that dimerize to form the active enzyme. The two primary isoforms are expressed equally. CASP10L contains an additional 43 amino acids at the end of the prodomain, but shares the same C terminus as the CASP10S isoform. The precise function of caspase-10 still remains poorly understood, though it is known that caspase-10 is recruited to both Fas- and TNFR-1 receptors in a FADD dependent manner. It is processed by caspase 8 cleavage and then goes on to cleave and activate caspases 3 and 7.

Somatic frameshift, nonsense and missense CASP10 mutations have been identified in patients with non-Hodgkin lymphoma [MIM:605027] and gastric cancer [MIM:613659], while germline mutations in CASP10 have been associated with type IIA autoimmune lymphoproliferative syndrome (ALPS2A) [MIM:603909]. This is thought to account for ~3-6% of all primary ALPS, with fewer than 20 patients reported in the literature thus far. Like other classic ALPS patients, most patients have early childhood onset of no n-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. Because of the condition's rarity, definitive correlations with genotypes or with elevation of the same biomarkers used for ALPS-FAS are lacking. Currently, few pathogenic or likely pathogenic germline CASP10 variants have been reported in the literature or found in ClinVar and even those reported remain controversial in terms of pathogenicity. At least ten variants, of which seven are missense (K99E, I406L, L285F, V410l, Y446C, P501L, L522l), have been identified in individuals with ALPS thus far (PMID: 10412980, 16446975, 27799292, 31309545). Additionally, at least one in/del resulting in a frameshift effect and a 13.4?kb intragenic CASP10 deletion have been reported, though the latter was found in a patient whose sJIA-like phenotype differed significantly from classical ALPS (PMID: 21382177). Most of the missense variants continue to remain controversial, given the conflicting data provided. K99E was reported in one patient and considered likely benign (PMID: 32599613). Zhu et al. (2006) showed that the I406L variant resulted in defective T cell apoptosis in vitro, double-negative T cell expansion, and positive direct antiglobulin IgG tests and antithyroid antibodies – findings present even in the asymptomatic carrier relatives of their affected proband and suggesting the need for a distinction between cellular and clinical penetrance (PMID: 16446975). They further showed that both L285F and I406L exerted dominant-negative effects in co-transfection assays into the H9 lymphocytic cell line. However, the pathogenicity of the I406L variant has been questioned because of its high allele frequency amongst some subpopulations in the ExAC database (PMID: 27535533), leading to its reclassification as a Variant of Uncertain Significance by some databases such as OMIM. In contrast, the same authors showed that V410I and Y446C exerted no dominant negative effects and were found at relatively high population allele frequencies, including in homozygosity in healthy controls. However, others have shown experimentally that T446C can decrease CASP10 protein activity (Dianzani et al, 1997; Ramenghi et al, 2000; Campagnoli et al, 2006; Zhu et al, 2006). Similarly, L522I is also found at high population frequencies, but has been predicted to be damaging and has also been associated with impaired apoptotic capacity (Hu et al, 2008). Miano et al. (2019) found that patients harboring V410I, Y446C, and L522I showed impaired Fas-mediated apoptosis (PMID: 31309545). Both homozygosity and heterozygosity for Y446C, V410l, and c.1202_1208del, p.(Cys401Leufs*15) have been reported. However, Consonni et al. (2024) showed that even though the last variant led to total loss of and reductions in caspase-10 RNA and protein, respectively, FAS-mediated apoptosis remained comparable to healthy controls (PMID: 38704374). Moreover, the authors did not find an [Load More]