Alternative titles; symbols
HGNC Approved Gene Symbol: CCHCR1
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,142,439-31,158,197 (from NCBI)
Linkage results from genomewide scans placed a major psoriasis susceptibility locus (see 177900) on chromosome 6p21.3, near the HLA-C locus (142840). Asumalahti et al. (2000) studied a gene from this region known as PG8 for 'putative gene-8,' a suggested tricohyalin homolog (Guillaudeux et al., 1998), or HCR for 'alpha-helix coiled-coil rod homolog' (Oka et al., 1999). The HCR gene encodes a protein of 757 amino acids. RT-PCR analysis showed that HCR was expressed at variable levels in all human tissues tested, more abundantly in heart, liver, skeletal muscle, kidney, and pancreas, and less so in lung and placenta.
Asumalahti et al. (2000) determined that the HCR gene contains 16 exons varying from 46 to 304 bp.
By genomic sequence analysis, Asumalahti et al. (2000) mapped the CCHCR1 gene to chromosome 6p21.3.
Asumalahti et al. (2000) found that the HCR gene is highly polymorphic, with at least 12 coding variants. The authors performed an association study among 100 Finnish psoriasis families of HCR polymorphisms and previously associated susceptibility alleles HLA-Cw*0602 and corneodesmosin (CDSN; 602593) allele 5 (CDSN*5). They found that 2 SNPs in exon 2 of HCR, arg77 to trp (R77W) and arg83 to trp (R83W), associated significantly with psoriasis and occurred together; they referred to this as the trp-trp allele (HCR*Trp-Trp). However, the HLA-Cw*0602 allele was rarer in controls and associated with a stronger relative risk. Association analysis did not support CD*5 as a psoriasis susceptibility allele in their sample. In addition, HCR was overexpressed in keratinocytes of psoriatic lesions compared with paired samples of healthy skin. The authors suggested a potential role for HCR in the pathogenesis of psoriasis. (In their original article, Asumalahti et al. (2000) had incorrectly termed the wildtype as trp rather than arg.)
Asumalahti et al. (2002) genotyped 419 psoriasis families at selected HLA loci. A conserved allele of HCR, *WWCC, was highly associated with psoriasis and with the HLA-Cw6 allele. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the 2 genes could not be genetically distinguished by this sample size. The variant HCR allele was predicted to differ in secondary structure from the wildtype protein by extending the length of the first alpha-helical loop. Furthermore, the pattern of HCR protein expression in lesional psoriatic skin differed from normal skin, as shown by immunocytochemistry. The authors hypothesized that the HCR*WWCC allele may be a major genetic determinant for psoriasis, possibly by impacting on keratinocyte proliferation.
O'Brien et al. (2001) investigated the HCR gene for disease association by direct sequencing of 9 PCR products amplified from a series of Swedish psoriasis patients and controls. They found that HCR is a highly polymorphic gene, with 25 polymorphisms in the open reading frame alone, of which 10 demonstrated disease association; however, the relationship between HCR polymorphisms and HLA-Cw*0602 indicated that HCR cannot truly be considered a likely candidate gene. They investigated the HLA-Cw*0602 association while stratifying for HCR single-nucleotide polymorphisms. They also investigated HCR single-nucleotide polymorphism association with the disease while stratifying for the presence of Cw*0602. O'Brien et al. (2001) found that for whichever single-nucleotide polymorphism that was stratified, there was still a strongly significant Cw*0602 association with psoriasis; however, when they stratified for Cw*0602 presence, only 1 silent polymorphism showed significant association. O'Brien et al. (2001) concluded that HCR polymorphisms display association with psoriasis due to linkage disequilibrium with Cw*0602 and are, therefore, unlikely to be directly involved in the development of psoriasis.
Elomaa et al. (2004) engineered transgenic mice with either a nonrisk allele of HCR or the HCR*WWCC risk allele under the control of the cytokeratin-14 (KRT14; 148066) promoter. Transgenic mice appeared phenotypically normal, and histologically their skin was indistinguishable from wildtype mice. Comparison of gene expression changes using microarrays between nonrisk and risk allele mice revealed similarities to previous observations in human psoriatic skin, including upregulation of cytokeratins 6 (KRT6A; 148041), 16 (KRT16; 148067) and 17 (KRT17; 148069) in risk allele mice. There were also changes in the expression of genes associated with terminal differentiation and formation of the cornified cell envelope. The authors concluded that HCR may constitute a susceptibility gene in the PSORS1 locus (177900).
By challenging the skin of CCHCR1 transgenic mice with wounding or TPA treatment, Tiala et al. (2008) showed that CCHCR1 regulates keratinocyte proliferation. Early wound healing on days 1 and 4 was delayed, and TPA-induced epidermal hyperproliferation was less pronounced in mice with the CCHCR1*WWCC risk allele than in mice with the normal allele or in wildtype animals. Overexpression of CCHCR1 affected basal keratinocyte proliferation, and CCHCR1*WWCC mice had less proliferating keratinocytes than the nonrisk allele mice. Similarly, keratinocytes isolated from risk allele mice proliferated more slowly in culture than in wildtype cells. Tiala et al. (2008) concluded that CCHCR1 is a regulator of keratinocyte proliferation.
Asumalahti, K., Laitinen, T., Itkonen-Vatjus, R., Lokki, M.-L., Suomela, S., Snellman, E., Saarialho-Kere, U., Kere, J. A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. Hum. Molec. Genet. 9: 1533-1542, 2000. Note: Erratum: Hum. Molec. Genet. 10: 301 only, 2001. [PubMed: 10888604] [Full Text: https://doi.org/10.1093/hmg/9.10.1533]
Asumalahti, K., Veal, C., Laitinen, T., Suomela, S., Allen, M., Elomaa, O., Moser, M., de Cid, R., Ripatti, S., Vorechovsky, I., Marcusson, J. A., Nakagawa, H., and 9 others. Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus. Hum. Molec. Genet. 11: 589-597, 2002. [PubMed: 11875053] [Full Text: https://doi.org/10.1093/hmg/11.5.589]
Elomaa, O., Majuri, I., Suomela, S., Asumalahti, K., Jiao, H., Mirzaei, Z., Rozell, B., Dahlman-Wright, K., Pispa, J., Kere, J., Saarialho-Kere, U. Transgenic mouse models support HCR as an effector gene in the PSORS1 locus. Hum. Molec. Genet. 13: 1551-1561, 2004. [PubMed: 15190014] [Full Text: https://doi.org/10.1093/hmg/ddh178]
Guillaudeux, T., Janer, M., Wong, G. K.-S., Spies, T., Geraghty, D. E. The complete genomic sequence of 424,015 bp at the centromeric end of the HLA class I region: gene content and polymorphism. Proc. Nat. Acad. Sci. 95: 9494-9499, 1998. [PubMed: 9689108] [Full Text: https://doi.org/10.1073/pnas.95.16.9494]
O'Brien, K. P., Holm, S. J., Nilsson, S., Carlen, L., Rosenmuller, T., Enerback, C., Inerot, A., Stahle-Backdahl, M. The HCR gene on 6p21 is unlikely to be a psoriasis susceptibility gene. J. Invest. Derm. 116: 750-754, 2001. [PubMed: 11348465] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01323.x]
Oka, A., Tamiya, G., Tomizawa, M., Ota, M., Katsuyama, Y., Makino, S., Shiina, T., Yoshitome, M., Iizuka, M., Sasao, Y., Iwashita, K., Kawakubo, Y., Sugai, J., Ozawa, A., Ohkido, M., Kimura, M., Bahram, S., Inoko, H. Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene. Hum. Molec. Genet. 8: 2165-2170, 1999. [PubMed: 10545595] [Full Text: https://doi.org/10.1093/hmg/8.12.2165]
Tiala, I., Wakkinen, J., Suomela, S., Puolakkainen, P., Tammi, R., Forsberg, S., Rollman, O., Kainu, K., Rozell, B., Kere, J., Saarialho-Kere, U., Elomaa, O. The PSORS1 locus gene CCHCR1 affects keratinocyte proliferation in transgenic mice. Hum. Molec. Genet. 17: 1043-1051, 2008. [PubMed: 18174193] [Full Text: https://doi.org/10.1093/hmg/ddm377]