Inherited palmoplantar keratodermas (PPKs) refer to a large and heterogeneous group of conditions resulting from abnormal epidermal differentiation and featuring thickening of the skin of the palms and soles. Here, we aimed at delineating the genetic basis of an autosomal recessive form of PPK manifesting with erythematous hyperkeratotic plaques over the palms and soles, extending to non-palmoplantar areas and associated with peripheral peeling of the skin. Whole exome sequencing revealed homozygous nonsense variants in the SERPINA12 gene in affected individuals. SERPINA12 encodes vaspin, a serine protease inhibitor. The SERPINA12 disease-causing variants were found to result in reduced vaspin expression in patient skin biopsies. SERPINA12 downregulation in three-dimensional skin equivalents was associated with marked epidermal acanthosis and hyperkeratosis, replicating the human phenotype. Moreover, decreased SERPINA12 expression resulted in reduced vaspin-mediated inhibition of kallikrein 7 activity as well as decreased levels of desmoglein-1 and corneodesmosin, two known kallikrein 7 substrates which have been previously implicated in the pathogenesis of PPKs and peeling skin syndromes. Taken collectively, the present data demarcate a novel type of autosomal recessive PPK, attribute to vaspin a role in skin biology and emphasize the importance of mechanisms regulating proteolytic activity for normal epidermal differentiation.

ESDR162 - Loss-of-function variants in SERPINA12 underlie autosomal recessive palmoplantar keratoderma

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING