Psoriasis 15, Pustular, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to pustular psoriasis-15 (PSORS15) is conferred by heterozygous mutation in the AP1S3 gene (615781) on chromosome 2q36.

For a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).

Setta-Kaffetzi et al. (2014) performed whole-exome sequencing in 9 patients with acral pustular psoriasis (acrodermatitis continua of Hallopeau) who were negative for mutation in the CARD14 (607211) and IL36RN (605507) genes, and identified heterozygosity for a missense mutation in the AP1S3 gene (R33W; 615781.0001) in 4 patients. Subsequent screening of 119 unrelated British patients with pustular psoriasis, including 112 with the palmoplantar form (PPP), 5 with the generalized form (GPP), and 2 with the acral form, revealed the same R33W missense mutation in 5 additional patients, 4 with PPP and 1 with GPP; in addition, 6 patients, 5 with PPP and 1 with GPP, were heterozygous for another missense mutation (F4C; 615781.0002) in the AP1S3 gene. Overall, Setta-Kaffetzi et al. (2014) observed that AP1S3 variants were detected in all forms of pustular psoriasis but were noticeably enriched among patients with the acral form and significantly underrepresented within the PPP dataset. Screening for the 2 variant alleles in 1,695 unrelated controls showed that the frequencies of both were significantly higher in patients with pustular psoriasis than in the general population. Haplotype analysis strongly suggested that both R33W and F4C are founder mutations in the European population; neither variant was detected in 72 Asian or 4 African patients with GPP. Segregation analysis in 2 representative pedigrees revealed that each proband, one with the R33W mutation and the other with the F4C mutation, had inherited the disease allele from an unaffected parent, indicating that environmental triggers such as infection, pregnancy, or drug exposure are likely required for disease development.