AP1S3 – Pustular Psoriasis 14

AP1S3 encodes the σ1C subunit of the adaptor protein complex 1 and has been implicated in autoinflammatory pustular psoriasis phenotypes, including acrodermatitis continua of Hallopeau and palmoplantar pustulosis (PPP). Heterozygous AP1S3 variants appear to contribute to disease risk through dysregulated keratinocyte autophagy and IL-36–mediated inflammation.

In genetic screens of 67 patients with pustular skin disease (generalized pustular psoriasis, acute generalized exanthematous pustulosis, and ACH), rare heterozygous AP1S3 coding variants such as c.11T>G (p.Phe4Cys) were identified in a small subset of cases (PMID:28887889). Broader sequencing in 258 individuals with palmoplantar pustulosis did not reveal additional AP1S3 mutations, and no family segregation data are reported.

In a cohort of 14 psoriasis patients with paradoxical reactions to TNF-α antagonists, comprehensive sequencing of AP1S3 exons and intronic flanks failed to detect pathogenic variants, suggesting locus heterogeneity and that AP1S3 mutations account for only a fraction of pustular phenotypes (PMID:34409641). A single case report of acrodermatitis continua treated with spesolimab demonstrated clinical efficacy but confirmed absence of AP1S3 coding variants in the index patient (PMID:39882245).

Functional studies in keratinocyte models have shown that loss of AP1S3 impairs autophagosome formation, leading to p62 accumulation, NF-κB activation, and overproduction of IL-36 cytokines. These cellular phenotypes were reversed by pharmacologic or genetic blockade of IL-36 signaling, mirroring clinical responses to IL-36 inhibitors in pustular psoriasis (PMID:27388993).

Collectively, the mechanistic data provide moderate support for AP1S3 haploinsufficiency as a driver of pustular skin inflammation. However, the genetic evidence is limited: only a few probands with heterozygous AP1S3 variants have been reported, without documented segregation or recurrence in independent families.

References

• Experimental Dermatology • 2023 • A viewpoint on the genetic determinants of generalised pustular psoriasis PMID:36645252
• The Journal of Investigative Dermatology • 2016 • AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production PMID:27388993
• The British Journal of Dermatology • 2018 • The genetic basis for most patients with pustular skin disease remains elusive PMID:28887889
• The Journal of Dermatology • 2021 • Clinical background of patients with psoriasiform skin lesions due to tumor necrosis factor antagonist administration at a single center. PMID:34409641
• Frontiers in Immunology • 2024 • Case report: Successful treatment with spesolimab of acrodermatitis continua of Hallopeau in an older patient without IL36RN mutations. PMID:39882245

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