Alternative titles; symbols
HGNC Approved Gene Symbol: CISH
SNOMEDCT: 252103004;
Cytogenetic location: 3p21.2 Genomic coordinates (GRCh38): 3:50,606,489-50,611,774 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.2 | {Bacteremia, susceptibility to} | 614383 | 3 | |
| {Malaria, susceptibility to} | 611162 | 3 | ||
| {Tuberculosis, susceptibility to} | 607948 | 3 |
CIS belongs to the suppressors of cytokine signaling (SOCS) family (see SOCS1; 603597) and is an important negative regulator for inflammatory signaling (Hu et al., 2009).
As part of the search for immediate-early cytokine-responsive genes, Yoshimura et al. (1995) cloned murine Cish, which was shown to have a growth inhibitory function. Cis, the protein product of Cish, has an Src homology 2 (SH2) domain in the middle of its sole structural motif.
Uchida et al. (1997) isolated a human CISH cDNA. The CISH protein consists of 258 amino acids. Northern blot analysis showed expression of CISH as a 2-kb transcript in various epithelial tissues, including lung and kidney.
Hu et al. (2009) noted that microRNAs (miRNAs) have been implicated in the fine tuning of the Toll-like receptor (TLR; see 603030)-mediated inflammatory response. Using Northern and Western blot analyses and PCR with human cholangiocytes, which express multiple TLRs, Hu et al. (2009) showed that the miRNAs MIR98 (300810) and LET7 (see MIRNLET7A1; 605386) regulated CIS protein expression via translational suppression. CIS expression was upregulated by lipopolysaccharide (LPS) or Cryptosporidium parvum exposure, and this upregulation involved downregulation of MIR98 and LET7, which relieved MIR98- and LET7-mediated translational repression of CIS. Gain- and loss-of-function studies showed that CIS accelerated degradation of IKBA (NFKBIA; 164008) and enhanced NFKB (see 164011) activation in cholangiocytes in response to LPS stimulation or C. parvum exposure. Hu et al. (2009) proposed that LET7 and MIR98 allow expression of CIS in response to microbial challenge.
Uchida et al. (1997) determined that the CISH gene contains 2 introns, about 3 kb and 0.4 kb in size, and has 3 repeats of the pentameric mRNA destabilization signal, ATTTA, in its 3-prime UTR.
Uchida et al. (1997) mapped the human CISH gene to chromosome 3p21.3 by FISH. The mouse gene is tightly linked to the Gnai2 gene (139360) on chromosome 9, a region syntenic to human chromosome 3p21.
Khor et al. (2010) used a case-control design to test for an association between CISH polymorphisms and susceptibility to major infectious diseases, including bacteremia, tuberculosis (607948), and severe malaria (611162), in blood samples from 8,402 persons from Gambia, Hong Kong, Kenya, Malawi, and Vietnam. The others had previously tested 20 other immune-related genes in 1 or more of these sample collections. Khor et al. (2010) observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all 5 SNPs, at positions -639, -292 (rs414171; 602441.0001), -163 (rs6768330), +1320 (rs2239751), and +3415 (rs622502), within the CISH-associated locus were considered together in a multiple-SNP score, Khor et al. (2010) found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P = 3.8 x 10(-11) for all comparisons), and with -292 accounting for most of the association signal (P = 4.58 x 10(-7)). Peripheral blood mononuclear cells (PBMCs) obtained from adult subjects carrying the -292 variant, as compared with wildtype cells, showed a muted response to the stimulation of interleukin-2 (IL2; 147680) production, i.e., 25 to 40% less CISH expression. Khor et al. (2010) found that the overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.
In a case-control study testing for association between CISH polymorphisms and susceptibility to major infectious diseases involving 8,402 individuals from Gambia, Hong Kong, Keyna, Malawi, and Vietnam, Khor et al. (2010) found that rs414171 at the -292 position relative to the CISH gene results in increased susceptibility to tuberculosis (607948), malaria (611162), and invasive bacterial disease (BACTS2; 614383) (p = 4.58 x -10(-7)). In addition, peripheral blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wildtype cells, showed a muted response to the stimulation of interleukin-2 (IL2; 147680), i.e., 25 to 40% less CISH expression.
Hu, G., Zhou, R., Liu, J., Gong, A.-Y., Eischeid, A. N., Dittman, J. W., Chen, X.-M. MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge. J. Immun. 183: 1617-1624, 2009. [PubMed: 19592657] [Full Text: https://doi.org/10.4049/jimmunol.0804362]
Khor, C. C., Vannberg, F. O., Chapman, S. J., Guo, H., Wong, S. H., Walley, A. J., Vukcevic, D., Rautanen, A., Mills, T. C., Chang, K.-C., Kam, K.-M., Crampin, A. C., and 23 others. CISH and susceptibility to infectious diseases. New Eng. J. Med. 362: 2092-2101, 2010. [PubMed: 20484391] [Full Text: https://doi.org/10.1056/NEJMoa0905606]
Uchida, K., Yoshimura, A., Inazawa, J., Yanagisawa, K., Osada, H., Masuda, A., Saito, T., Takahashi, T., Miyajima, A., Takahashi, T. Molecular cloning of CISH, chromosome assignment to 3p21.3, and analysis of expression in fetal and adult tissues. Cytogenet. Cell Genet. 78: 209-212, 1997. [PubMed: 9465889] [Full Text: https://doi.org/10.1159/000134658]
Yoshimura, A., Ohkubo, T., Kiguchi, T., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Hara, T., Miyajima, A. A novel cytokine-inducible gene CIS, encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 14: 2816-2826, 1995. [PubMed: 7796808] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb07281.x]