PSORS15

PSORS15 (PSORS15 stands for: Psoriasis Susceptibility 15) is a genetic locus associated with psoriasis. The gene is located on chromosome 2q36.

Pustular psoriasis susceptibility is caused by a heterozygous mutation in the AP1S3 gene (615781) on chromosome 2q36.

Setta-Kaffetzi et al (2014) performed whole exome sequencing in 9 patients with acrodermatitis continua suppurativa who had no 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.

The AP1S3 variant was detectable in all forms of pustular psoriasis, but was significantly more common in patients with the acral form (Setta-Kaffetzi et al. 2014). Screening for the two allele variants in 1,695 unrelated controls showed that the frequency of both alleles was 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; no variant was detected in 72 Asian or 4 African patients with GPP. Segregation analysis in two 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, suggesting that environmental triggers such as infections, pregnancy or drug exposures are likely required for disease development.

Mossner et al (2018) sequenced the IL36RN, CARD14 and AP1S3 genes in 61 patients with GPP, 2 with acute generalized exanthematous pustulosis (AGEP) and 4 with acrodermatitis continua suppurativa Hallopeau and examined 258 patients with PPP for coding changes in AP1S3. The majority of patients with GPP did not carry rare variants in any of the three genes, indicating further genetic heterogeneity in generalized pustular psoriasis.

Three patients with PPP, one with AGEP and one with GPP were heterozygous for the R33W mutation in the AP1S3 gene; the patient with GPP was also homozygous for a missense mutation in the IL36RN gene (S113L; 605507.0002).

Ten patients with PPP, one with AGEP and one with GPP were heterozygous for the F4C mutation in AP1S3; the patient with GPP was also compound heterozygous for the S113L mutation and a 56-bp deletion in IL36RN.

The authors suspect that pustular psoriasis is based on a complex inheritance pattern.

1. Mossner R et al (2018) The genetic basis for most patients with pustular skin disease remains elusive. Brit J Derm 178: 740-748
2. Setta-Kaffetzi N et al.(2014) AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. Am J Hum Genet 94: 790-797.