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Abstract：
Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo-plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis-localization, leading to enhanced epidermal desquamation. We investigated two Arab-Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo-plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis-localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age- and gender-matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling.
摘要：
肢端剥皮综合征（APSS）是一组异质性的遗传性皮肤病，表现为掌-足底皮肤脱落，偶尔伴有红斑和表皮增厚。APSS的一个子集是由蛋白酶抑制剂编码基因的突变引起的，导致无相反的蛋白酶活性和桥粒降解和/或错误定位，导致表皮脱屑增强。我们调查了两个自婴儿期以来患有轻度角化皮病和明显的APSS的阿拉伯穆斯林兄弟姐妹。遗传分析揭示了SERPINB7的纯合突变，c.796C>T，这是Nagashima型掌-足底角化病（NPPK）的创始人突变。虽然以前没有正式报道，在其他NPPK患者中发现了APSS。我们假设SERPINB7功能的丧失可能通过角质形成细胞粘附受损而导致剥离表型。与引起APSS的其他蛋白酶抑制剂突变相似。与年龄和性别匹配的健康对照的活检相比，在患者足底活检中观察到桥粒成分的错误定位。正常人表皮角质形成细胞中SERPINB7的沉默导致机械应力下细胞片碎片增加。免疫染色显示桥粒糖蛋白1和桥粒糖蛋白1的表达降低。这项研究表明，除了角质层扰动，SERPINB7的丢失会破坏桥粒成分，这可能会导致脱皮，表现为皮肤脱皮。
