A novel SERPINA12 variant and first European patients with diffuse palmoplantar keratoderma

Area of Science:

• Genetics
• Dermatology
• Biochemistry

Background:

• Hereditary palmoplantar keratodermas (hPPKs) are skin disorders marked by persistent palmoplantar hyperkeratosis.
• Loss-of-function variants in SERPINA12 are linked to autosomal recessive diffuse hPPK, sharing traits with Nagashima-type PPK (NPPK) caused by SERPINB7 variants.

Purpose of the Study:

• To deepen the understanding of clinical and genetic aspects of serine protease-related hPPKs stemming from SERPINA12 and SERPINB7 variants.

Main Methods:

• Whole-exome sequencing (WES) was employed for hPPK patients.
• Haplotype analysis was conducted for families with recessive SERPINA12 variants.
• A literature review of SERPINA12- and SERPINB7-related hPPKs was performed.

Main Results:

• Three new European patients with SERPINA12-related hPPK were identified, confirming the phenotype and revealing a novel missense variant (c.1100G>A p.(Gly367Glu)).
• The SERPINA12 variant c.631C>T p.(Arg211*) showed enrichment in the Finnish population, suggesting a founder effect.
• Patients with SERPINA12 and SERPINB7 variants exhibited similar phenotypes, including diffuse transgradient PPK, palmoplantar hyperhidrosis, and aquagenic whitening, making them clinically indistinguishable without genetic analysis.

Conclusions:

• Recessive SERPINA12 and SERPINB7 variants lead to protease overactivity and a similar hPPK phenotype that requires genetic analysis for differentiation.
• SERPINA12 variants should be investigated in non-Asian individuals presenting with diffuse transgradient PPK.
• Studying serine protease inhibitors offers insights into the proteolytic network governing epidermal homeostasis.