DO: 0080475;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q25.3 | Psoriasis 2 | 602723 | Autosomal dominant | 3 | CARD14 | 607211 |
A number sign (#) is used with this entry because of evidence that psoriasis-2 (PSORS2) is caused by heterozygous mutation in the CARD14 gene (607211) on chromosome 17q25.
For a phenotypic description and a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).
Hwu et al. (2005) studied a large 5-generation Taiwanese kindred in which 16 of 93 family members had classic skin manifestations of psoriasis and 10 had mild skin lesions. The age of onset and severity of disease varied in family members. The proband was a 41-year-old woman who developed plaque-like scaling skin lesions at 10 years of age and had cracking and fissuring over most of her skin surface, including her palms and scalp, whereas her son had erythrodermic psoriasis with generalized, inflamed erythematous lesions and fever. An affected female second cousin had well-demarcated, palm-sized, pink-to-red skin lesions noted since 3 years of age, extending from her extremities to trunk within 6 months of follow-up. However, her father and some other family members exhibited only ichthyosis (see 242300)-like skin lesions over their legs, or lesions over the extensor side of their knuckles, elbows, and knees. Diffuse skin atrophy was seen in older patients. No active arthritis was seen in this kindred, but some patients had deformed finger joints and had experienced arthralgia during disease flare-ups. Skin biopsy specimens from the proband's son revealed marked hyperkeratosis and parakeratosis with follicular plugging, loss of granular layer, epidermal acanthosis, elongation of rete ridges, thin suprapapillary plates, vascular dilation, and inflammatory cell infiltration in the dermis and epidermis. In the female second cousin there were similar but less severe histologic changes, with alternating orthokeratosis and parakeratosis reminiscent of pityriasis rubra pilaris (173200).
Using polymorphic microsatellite markers in a study of 8 multiply affected psoriasis kindreds, Tomfohrde et al. (1994) localized a gene involved in psoriasis susceptibility to distal 17q. In the family that showed the strongest evidence for linkage (family PS1), the recombination fraction between a psoriasis susceptibility locus and D17S784 was 0.04 with a maximum 2-point lod score of 5.33. There was also evidence for genetic heterogeneity, and although none of the linked families showed any association with HLA-Cw6, 2 unlinked families showed weak association. Tomfohrde et al. (1994) estimated that half the families were unlinked to 17q.
In a large and extensively affected family from the northeast of England, Matthews et al. (1995) excluded linkage between the telomeric region of 17q and psoriasis. Using 24 multiplex psoriasis kindreds and 12 microsatellite markers on chromosome 17, Nair et al. (1995) could find no evidence of linkage to the previously implicated marker D17S784 under any of 8 models varying in mode of inheritance, penetrance, and sporadic cases. All other chromosome 17 markers tested also failed to detect evidence for linkage in any of the kindreds. Although further analysis using affected sib pair methods provided no statistically significant evidence for linkage to any chromosome 17 marker, a cluster of 3 distal 17q loci displayed a trend towards greater than expected allele-sharing values. While not formally confirming the existence of a psoriasis susceptibility locus on the distal long arm of chromosome 17, the results suggested possible involvement under a polygenic model.
In a 12.5-cM genomewide scan for psoriasis susceptibility loci using recombination-based tests and allele-sharing methods, Nair et al. (1997) confirmed the previous report of a dominant susceptibility locus on distal 17q.
In a comprehensive multipoint parametric and nonparametric linkage analysis in 104 Swedish psoriasis families (153 sib pairs), Enlund et al. (1999) found only suggestive linkage to 17q.
Speckman et al. (2003) stated that the PSORS2 locus maps to chromosome 17q25. To refine the location of PSORS2, they genotyped 242 primarily nuclear families for 15 polymorphic microsatellites mapping to 17q23-q25. Nonparametric linkage analysis revealed a linkage peak lying close to a novel cluster of genes from the immunoglobulin superfamily. This cluster spans more than 250 kb and harbors 5 CMRF35-like genes, including CMRF35A1 (606790), and a sixth inhibitory receptor, CMRF35H (606790). Speckman et al. (2003) provided GenBank sequence numbers for CMRF35A2-6.
Helms et al. (2003) described 2 peaks of strong association with psoriasis on 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (604990) and NAT9, a member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association found by Helms et al. (2003) was located in the gene encoding the regulatory associated protein of MTOR (RAPTOR; 607130). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 (151385) binding. Other examples of loss of a RUNX1 binding site in association with susceptibility to an autoimmune disease have been reported for systemic lupus erythematosus (see PDCD1, 600244) and rheumatoid arthritis (see SLC22A4, 604190).
In a dataset of 233 parent-offspring trios with psoriasis, Capon et al. (2004) analyzed 8 representative SNPs selected from both of the association peaks identified by Helms et al. (2003) and found evidence for association only at RAPTOR rs2019154 (p = 0.027). Restricting the analysis to 116 trios with a well-documented family history of psoriasis increased the significance of the association for 3 RAPTOR SNPs, with rs2019154 yielding a p value of 0.008.
In a large 5-generation family with psoriasis, Hwu et al. (2005) performed a genomewide scan with polymorphic microsatellite markers on 43 DNA samples from 13 family members with classic manifestations, 10 with mild skin lesions, 7 with unknown disease status, and 13 unaffected family members. Highly significant linkage with a maximum 2-point lod score of 7.164 (theta = 0.01) and a multipoint lod score of 4.58 was found at D17S928, the most telomeric microsatellite marker at 17q. Fine mapping using 202 SNPs followed by modified pedigree disequilibrium test analysis revealed a strong association (p = 0.0008) between psoriasis and rs3744165, located within 400 kb of the 17q terminus. Hwu et al. (2005) noted that this locus is distal to and distinct from the previously reported putative susceptibility gene SLC9A3R1 at 17q25.
In a study of 579 pedigrees with psoriasis, Stuart et al. (2006) found no evidence for a disease association with 3 RUNX1-binding site SNPs or a haplotype formed by the 3 SNPS or with 3 RAPTOR SNPs or a haplotype formed by the 3 RAPTOR SNPs. However, the authors did find evidence for linkage to distal 17q, with lod scores greater than 2 at marker D17S785 located 1.7 cM distal to the RUNX1 SNPs.
Exclusion Studies
By SNP analysis, Giardina et al. (2006) excluded linkage to the PSORS2 locus in 245 Italian patients with psoriatic arthritis (see 607507).
Using DNA from members of a family with psoriasis mapping to chromosome 17qter, originally studied by Tomfohrde et al. (1994) (family PS1), Jordan et al. (2012) performed exome, targeted-capture, and next-generation sequencing and identified a heterozygous missense mutation in the CARD14 gene (G117S; 607211.0001) that segregated with the disease. Sequencing CARD14 in the Taiwanese psoriasis family reported by Hwu et al. (2005) revealed a heterozygous splice site mutation (607211.0002) that segregated with the disease. In addition, heterozygosity for a de novo CARD14 missense mutation (D138A; 607211.0003) was identified in a 3-year-old Haitian girl with pustular psoriasis. Jordan et al. (2012) also identified a variant in the SLC26A11 gene (610117) on chromosome 17q25 that segregated with disease in family PS1; no mutations in SLC26A11 were detected in the Taiwanese family or in the Haitian patient, and the authors stated that further investigation would be required to determine whether or not the SLC26A11 variant identified in family PS1 contributes independently to psoriasis or psoriatic arthritis.
To determine whether additional rare variants in the CARD14 gene predispose to psoriasis, Jordan et al. (2012) screened 7 psoriasis cohorts involving more than 6,000 cases and 4,000 controls and identified 15 additional rare missense variants that were enriched in cases compared to controls (burden test, p = 0.0015; variable threshold test, p = 0.0053). Two of the rare variants were not found in controls and manifested as overtly causative (607211.0004 and 607211.0005). Metaanalysis revealed an association between psoriasis and SNP rs11652075 (R820W; p = 2.1 x 10(-6)), and evidence for association increased in 2 cohorts of European ancestry when the PSORS1 (177900) variant HLA-Cw*0602 (SNP rs10484554) was included as a covariate, suggesting a genetic connection between PSORS1 and PSORS2. In addition, Jordan et al. (2012) observed a wide range of phenotypes even among individuals with the same CARD14 substitution, indicating that genetic background and/or environmental factors may be involved.
Capon, F., Helms, C., Veal, C. D., Tillman, D., Burden, A. D., Barker, J. N., Bowcock, A. M., Trembath, R. C. Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. (Letter) J. Med. Genet. 41: 459-460, 2004. [PubMed: 15173233] [Full Text: https://doi.org/10.1136/jmg.2004.018226]
Enlund, F., Samuelsson, L., Enerback, C., Inerot, A., Wahlstrom, J., Yhr, M., Torinsson, A., Martinsson, T., Swanbeck, G. Analysis of three suggested psoriasis susceptibility loci in a large Swedish set of families: confirmation of linkage to chromosome 6p (HLA region), and to 17q, but not to 4q. Hum. Hered. 49: 2-8, 1999. [PubMed: 9858851] [Full Text: https://doi.org/10.1159/000022832]
Giardina, E., Predazzi, I., Sinibaldi, C., Peconi, C., Amerio, P., Costanzo, A., Paradisi, A., Capizzi, R., Paradisi, M., Chimenti, S., Taccari, E., Novelli, G. PSORS2 markers are not associated with psoriatic arthritis in the Italian population. Hum. Hered. 61: 120-122, 2006. [PubMed: 16733365] [Full Text: https://doi.org/10.1159/000093529]
Helms, C., Cao, L., Krueger, J. G., Wijsman, E. M., Chamian, F., Gordon, D., Heffernan, M., Wright Daw, J. A., Robarge, J., Ott, J., Kwok, P.-Y., Menter, A., Bowcock, A. M. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nature Genet. 35: 349-356, 2003. [PubMed: 14608357] [Full Text: https://doi.org/10.1038/ng1268]
Hwu, W.-L., Yang, C.-F., Fann, C. S. J., Chen, C.-L., Tsai, T.-F., Chien, Y.-H., Chiang, S.-C., Chen, C.-H., Hung, S.-I., Wu, J.-Y., Chen, Y.-T. Mapping of psoriasis to 17q terminus. (Letter) J. Med. Genet. 42: 152-158, 2005. [PubMed: 15689454] [Full Text: https://doi.org/10.1136/jmg.2004.018564]
Jordan, C. T., Cao, L., Roberson, E. D. O., Duan, S., Helms, C. A., Nair, R. P., Duffin, K. C., Stuart, P. E., Goldgar, D., Hayashi, G., Olfson, E. H., Feng, B.-J., and 14 others. Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappa-B, in psoriasis. Am. J. Hum. Genet. 90: 796-808, 2012. [PubMed: 22521419] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.013]
Jordan, C. T., Cao, L., Roberson, E. D. O., Pierson, K. C., Yang, C.-F., Joyce, C. E., Ryan, C., Duan, S., Helms, C. A., Liu, Y., Chen, Y., McBride, A. A., Hwu, W.-L., Wu, J.-Y., Chen, Y.-T., Menter, A., Goldbach-Mansky, R., Lowes, M. A., Bowcock, A. M. PSORS2 is due to mutations in CARD14. Am. J. Hum. Genet. 90: 784-795, 2012. [PubMed: 22521418] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.012]
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Nair, R. P., Henseler, T., Jenisch, S., Stuart, P., Bichakjian, C. K., Lenk, W., Westphal, E., Guo, S.-W., Christophers, E., Voorhees, J. J., Elder, J. T. Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. Hum. Molec. Genet. 6: 1349-1356, 1997. [PubMed: 9259283] [Full Text: https://doi.org/10.1093/hmg/6.8.1349]
Speckman, R. A., Wright Daw, J. A., Helms, C., Duan, S., Cao, L., Taillon-Miller, P., Kwok, P.-Y., Menter, A., Bowcock, A. M. Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum. Genet. 112: 34-41, 2003. [PubMed: 12483297] [Full Text: https://doi.org/10.1007/s00439-002-0851-y]
Stuart, P., Nair, R. P., Abecasis, G. R., Nistor, I., Hiremagalore, R., Chia, N. V., Qin, Z. S., Thompson, R. A., Jenisch, S., Weichenthal, M., Janiga, J., Lim, H. W., Christophers, E., Voorhees, J. J., Elder, J. T. Analysis of RUNX1 binding site and RAPTOR polymorphisms in psoriasis: no evidence for association despite adequate power and evidence for linkage. J. Med. Genet. 43: 12-17, 2006. [PubMed: 15923274] [Full Text: https://doi.org/10.1136/jmg.2005.032193]
Tomfohrde, J., Silverman, A., Barnes, R., Fernandez-Vina, M. A., Young, M., Lory, D., Morris, L., Wuepper, K. D., Stastny, P., Menter, A., Bowcock, A. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science 264: 1141-1145, 1994. [PubMed: 8178173] [Full Text: https://doi.org/10.1126/science.8178173]