据报道,丝氨酸蛋白酶抑制剂B7(SERPINB7)突变会导致Nagashima型掌plant角化病(NPPK),但是它们的生物学效应在很大程度上是未知的。我们进行了全外显子组测序,鉴定出c.796C>T(p。中国家系中SERPINB7的Arg266Ter)突变,表现为常染色体隐性遗传模式。我们评估了SERPINB7在纯合和杂合突变携带者中的功能,结果表明,单个c.796C>T突变可能会改变SERPINB7的亚细胞定位。其中一名纯合突变患者(II-3)接受了ixekizumab治疗,并显示角质化的适度改善。此外,我们分析了人类SERPINB7的斑马鱼同源物serpinb1l1和serpinb1l3的时空表达,它们在幼虫和成虫中表达。在幼虫中,serpinb1l1和serpinb1l3均在消化道中表达。然后,我们根据与人类NPPK表达位点的相似性对成年鳍进行了RT-PCR,发现这些基因在五个鳍中表达(胸肌,骨盆,背侧,肛门,和尾端)斑马鱼远端。一起来看,我们的结果表明,单个c.796C>T(p。Arg266Ter)突变可能会改变SERPINB7编码蛋白在皮肤中的位置,而斑马鱼SERPINB7同源物在成年鳍中表达。这些发现将使我们能够构建敲除模型来探索掌plant角化病的发病机理。
Serine protease inhibitor B7 (
SERPINB7) mutations have been reported to cause Nagashima-type palmoplantar keratosis (NPPK), but their biological effects are largely unknown. We conducted whole-exome sequencing and identified a c.796C>T (p.Arg266Ter) mutation in
SERPINB7 in a Chinese pedigree, which presented as an autosomal recessive inheritance pattern. We assessed the function of
SERPINB7 in homozygous and heterozygous mutation carriers, and the results suggested that the single c.796C>T mutation may alter the subcellular localization of
SERPINB7. One of the homozygous mutation patients (II-3) was treated with ixekizumab and showed moderate improvement in keratinization. In addition, we analysed the spatiotemporal expression of serpinb1l1 and serpinb1l3, the zebrafish homologue of human SERPINB7, which is expressed in larvae and adults. In larvae, both serpinb1l1 and serpinb1l3 were expressed in the digestive tract. Then, we performed RT-PCR on adult fins based on similarity to the site of NPPK expression in humans and found that the genes were expressed in five fins (pectoral, pelvic, dorsal, anal and caudal) of the zebrafish distal extremity. Taken together, our results demonstrated that the single c.796C>T (p.Arg266Ter) mutation may alter the location of SERPINB7-encoded protein in the skin, while zebrafish
SERPINB7 homologue was expressed in adult fins. These findings will enable us to construct knock-out models to explore the pathogenesis of palmoplantar keratosis.