Alt. symbols: PSORS15

Approved name: adaptor related protein complex 1 subunit sigma 3
Alt. names: adaptor related protein complex 1 sigma 3 subunit

Location: 2q36.1: 223667680 - 223838027 (-)
Gene type: protein_coding, 18 transcripts.

Scores: LoFtool: 0.438000 | pLI: 0.16745018 | LOEUF: 1.079

HGNC: 18971

NCBI: 130340, RefSeq: NG_034017.1

Ensembl: ENSG00000152056.18

LRG_ | Status: none

OMIM: 615781

Expression | ProteinAtlas

AP1S3 encodes a subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. AP1S3 is a core AP-1 subunit that is predicted to stabilize AP-1 heterotetramers. Setta-Kaffetzi et al. (2014) found that AP1S3 is important for proper vesicular trafficking of TLR-3 (Toll-like receptor 3) and its downstream signaling (PMID: 24791904).

Heterozygous missense mutations in AP1S3 have been associated with susceptibility to pustular psoriasis [OMIM: 616106], an autoinflammatory condition also associated with genetic variation in IL36RN, CARD14, and MPO (PMID: 33955502). They are all thought to share an underlying pathogenesis linked to IL-1/IL-36 dysregulation. By screening patients with different forms of pustular psoriasis via whole exome sequencing, Setta-Kaffetzi et al. (2014) identified two missense variants - R33W and F4C ? i n AP1S3 (PMID: 24791904). They noted that these variants could be found in all forms of pustular psoriasis, but were noticeably enriched among patients with the acral form versus the plantopalmar form (PPP). Screening for these 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, while haplotype analysis strongly suggested that both R33W and F4C are founder mutations in the European population. These AP1S3 pathogenic variants are rarely found non-Europeans such as East Asians, and the variant frequency of AP1S3 in GPP patients of European descent is estimated at 10.8%. Segregation analysis in 2 representative pedigrees found 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 additional environmental triggers are likely required for disease development. Mossner et al. (2018) then screened for variants in IL36RN, CARD14, and AP1S3 in patients with PPP, generalized pustular psoriasis (GPP), acute generalized exanthematous pustulosis (AGEP), and acrodermatitis continua of Hallopeau. They identified heterozygosity for the R33W mutation in 3 patients with PPP, 1 with AGEP, and 1 with GPP, though the patient with GPP was also homozygous for an IL36RN missense mutation (S113L). Heterozygosity for the F4C mutation was found in 10 patients with PPP, 1 with AGEP, and 1 with GPP, with the last also compound heterozygous for the S113L mutation and a 56-bp deletion in IL36RN. Thus, the authors proposed that pustular psoriasis may result from a complex inheritance pattern that is likely oligogenic (PMID: 28887889). Similarly, Twelves et al. (2019) found that 8 out of 251 GPP cases carry heterozygous F4C (4 cases) or R33W (4 cases) mutations, with two F4C carriers also harboring known pathogenic IL36RN variants. [Load More]