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

Abstract

BackgroundHereditary palmoplantar keratodermas (hPPKs) comprise a heterogeneous group of skin disorders characterized by persistent palmoplantar hyperkeratosis. Loss‐of‐function variants in a serine peptidase inhibitor, SERPINA12, have recently been implicated in autosomal recessive diffuse hPPK. The disorder appears to share similarities with another hPPK associated with protease overactivity, namely Nagashima‐type PPK (NPPK) caused by biallelic variants in SERPINB7.ObjectivesThe aim of this study was to enhance the understanding of the clinical and genetic characteristics of serine protease‐related hPPKs caused by variants in SERPINA12 and SERPINB7.MethodsWhole‐exome sequencing (WES) was performed for hPPK patients. Haplotype analysis was completed for the patients with identified recessive SERPINA12 variants and their available family members. In addition, the current literature of SERPINA12‐ and SERPINB7‐related hPPKs was summarized.ResultsThe phenotype of SERPINA12‐related hPPK was confirmed by reporting three new SERPINA12 patients, the first of European origin. A novel SERPINA12 c.1100G>A p.(Gly367Glu) missense variant was identified confirming that the variant spectrum of SERPINA12 include both truncating and missense variants. The previously reported SERPINA12 c.631C>T p.(Arg211*) was indicated enriched in the Finnish population due to a plausible founder effect. In addition, SERPINA12 hPPK patients were shown to share a similar phenotype to patients with recessive variants in SERPINB7. The shared phenotype included diffuse transgradient PPK since birth or early childhood and frequent palmoplantar hyperhidrosis, aquagenic whitening and additional hyperkeratotic lesions in non‐palmoplantar areas. SERPINA12 and SERPINB7 hPPK patients cannot be distinguished without genetic analysis.ConclusionsRecessive variants in SERPINA12 and SERPINB7 leading to protease overactivity and hPPK produce a similar phenotype, indistinguishable without genetic analysis. SERPINA12 variants should be assessed also in non‐Asian patients with diffuse transgradient PPK. Understanding the role of serine protease inhibitors will provide insights into the complex proteolytic network in epidermal homeostasis.

SERPINA12‐associated palmoplantar keratoderma may be prevalent across different populations

“…SERPINB7-associated PPKs are clinically indistinguishable, suggesting the necessity of genetic evaluation. 7 The study by Brandt et al expands the spectrum of pathogenic SERPINA12 variants, and further underscores the crucial roles of serine protease inhibitors in maintaining normal differentiation of the palmoplantar epidermis in humans.…”

“…Of these, two patients were homozygous for a recurrent nonsense variant c.631C > T (p.Arg211*), while one was compound heterozygous for the variant c.631C > T and a novel missense variant c.1100G > A (p.Gly367Glu). 7 Therefore, the authors have revealed, for the first time, that there are patients with the SERPINA12-associated PPK in European populations. Furthermore, they clearly showed that the c.631C > T in the SERPINA12 was a founder variant in the Finnish population.…”

“…Furthermore, they clearly showed that the c.631C > T in the SERPINA12 was a founder variant in the Finnish population. 7 It can be postulated that the c.631C > T is a common founder variant across different populations since it was previously identified in a patient of Arab origin as well. 5 The c.1100G > A (p.Gly367Glu) is the first pathogenic missense variant located within the RCL of SERPINA12 protein.…”

“…Notably, this study nicely summarized clinical features of all the previously reported cases of SERPINA12-and SERPINB7-associated PPKs in order to perform detailed comparison of the phenotypes between the two groups. 7 It has turned out that SERPINA12 and SERPINB7 patients almost completely share the clinical features including diffuse transgradient PPK, frequent palmoplantar hyperhidrosis, palmoplantar skin peeling and aquagenic whitening. Histopathological features also resemble between the two groups.…”

“…The study, presented by Brandt et al, 7 in this issue aimed to characterize serine protease inhibitor-associated PPKs in both clinical and genetic aspects. They analysed three Finnish patients with an autosomal recessive form of diffuse transgradient PPK, and identified biallelic pathogenic SERPINA12 variants in all the three affected individuals.…”