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

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. Whole exome sequencing revealed in affected individuals homozygous nonsense variants in the SERPINA12 gene. SERPINA12 encodes the visceral adipose tissue-derived serpin A12 (vaspin), a serine protease inhibitor. SERPINA12 downregulation in three-dimensional skin equivalents was associated with marked epidermal acanthosis and hyperkeratosis, replicating the human phenotype. In addition, 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 are required for normal epidermal differentiation. Taken collectively, the present data demarcate a new 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.