The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

遗传性皮肤病的遗传原因的发现对于理解表皮分化、功能和更新至关重要。在这里，我们通过外显子组测序显示ASPRV1（天冬氨酸肽酶逆转录病毒样 1）中的突变导致显性孟德尔疾病，其特征是掌跖角化病和板层鱼鳞病，这是一种完全隐性的表型。ASPRV1编码一种哺乳动物特异性和分层上皮特异性蛋白酶，在丝聚蛋白的加工中很重要，丝聚蛋白是最上表皮层的关键成分。三个不同的杂合ASPRV1四个不相关的鱼鳞病家族中的错义突变与疾病分离，并破坏彼此非常接近的蛋白质残基和自催化切割位点。突变 ASPRV1 蛋白的表达表明，所有三种突变都会改变 ASPRV1 自动切割和聚丝蛋白加工，这是对表皮屏障完整性至关重要的功能。