AP1S3 – Pustulosis Palmaris et Plantaris

Rare heterozygous AP1S3 variants have been reported in patients with pustulosis palmaris et plantaris (PPP), with sequencing of 258 PPP probands identifying two rare missense changes (c.11T>G (p.Phe4Cys), c.97C>T (p.Arg33Trp)) in two individuals without reported segregation ([PMID:28887889]). The recurrent localization of these variants at the N-terminus of the AP1S3 subunit suggests a potential hotspot for functional disruption. No additional affected family members have been described for AP1S3-related PPP. Experimental studies in keratinocytes demonstrate that AP1S3 deficiency impairs autophagosome formation, leading to accumulation of the p62 adaptor and overactivation of NF-κB signaling, with consequent up-regulation of IL-36 cytokines (IL-36α, IL-36β, IL-36γ) ([PMID:27388993]). These cellular phenotypes mirror the inflammatory features observed in PPP lesions. Rescue of autophagy defects by IL-36 blockade further supports a pathogenic role for AP1S3 loss-of-function. Collectively, current data indicate a limited but emerging association between heterozygous AP1S3 variants and PPP, warranting further familial and functional studies to establish definitive clinical validity.

References

• The British journal of dermatology • 2018 • The genetic basis for most patients with pustular skin disease remains elusive. PMID:28887889
• The Journal of investigative dermatology • 2016 • AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production. PMID:27388993

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