Inherited palmoplantar keratodermas 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 palmoplantar keratodermas manifesting with erythematous hyperkeratotic plaques over the palms and soles, extending to non-palmoplantar areas. Whole-exome sequencing in affected individuals revealed homozygous nonsense variants in the SERPINA12 gene. SERPINA12 encodes the visceral adipose tissue-derived serpin A12, a serine protease inhibitor. The pathogenic variants were found to result in reduced visceral adipose tissue-derived serpin A12 expression in patients’ skin biopsies in comparison to healthy controls. 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 visceral adipose tissue-derived serpin A12-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. The present data, taken collectively, demarcate a unique type of autosomal recessive palmoplantar keratodermas, attribute to visceral adipose tissue-derived serpin A12 a role in skin biology, and emphasize the importance of mechanisms regulating proteolytic activity for normal epidermal differentiation.

遗传性掌plant角化病是指由异常表皮分化引起的一大类异质性疾病，特征是手掌和脚掌皮肤增厚。在这里，我们的目的是勾勒出掌plant角化病的常染色体隐性形式的遗传基础，该病表现为手掌和脚底红斑性角化过度斑块，并延伸至非pal掌区域。受影响个体的全外显子测序揭示了SERPINA12基因的纯合性无意义变异。SERINAA12编码内脏脂肪组织衍生的丝氨酸蛋白酶抑制剂A12（一种丝氨酸蛋白酶抑制剂）。与健康对照组相比，发现病原体变异导致患者皮肤活检中内脏脂肪组织衍生的丝氨酸蛋白酶抑制剂A12表达降低。此外，三维皮肤等效物中SERPINA12的下调与明显的表皮棘皮症和角化过度有关，从而复制了人类表型。此外，SERPINA12减少表达导致内脏脂肪组织衍生的丝氨酸蛋白酶抑制剂A12介导的激肽释放酶7活性的抑制作用降低，以及降低desmoglein-1和角质形成素的水平，这两种已知的激肽释放酶7底物是正常表皮分化所必需的。共同获得的本数据划定了一种独特类型的常染色体隐性掌plant性角化皮炎，归因于内脏脂肪组织衍生的丝氨酸蛋白酶抑制剂A12在皮肤生物学中的作用，并强调了调节蛋白水解活性对正常表皮分化的机制的重要性。