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

BACKGROUND: 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.

OBJECTIVE: 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.

METHODS: We used whole exome and direct sequencing, qRT-PCR, immunostaining, three-dimensional skin equivalents, immunoblotting, ELISA, TUNEL and kallikrein 7 activity assays.

RESULTS: Whole exome sequencing revealed homozygous nonsense variants in SERPINA12 in affected individuals. SERPINA12 encodes the visceral adipose tissue-derived serpin A12 (vaspin), a serine protease inhibitor. The pathogenic variants were found to result in reduced vaspin expression in patients skin. In addition, 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 are required for normal epidermal differentiation.

CONCLUSION: 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.