关键词: 家族性进行性色素沉着症, 解聚素与金属蛋白酶10, 连锁分析, 外显子测序

Abstract: 【Abstract】 Objective To identify the causative gene in patients with familial progressive hyperpigmentation （FPH）. Methods Two families with FPH were collected in March 2005 and March 2015 respectively, and their phenotypes were observed and recorded. The causative gene was investigated by single nucleotide polymorphism （SNP）-based genome-wide linkage analysis and exome sequencing, and verified by Sanger sequencing. The candidate gene expression was determined in FPH lesions and normal skin tissues by using immunohistochemical techniques. Results The genome-wide linkage analysis showed that the causative gene in FPH family 1 was mapped to the loci of rs1026369-rs11857925 on chromosome 15q21.1 - q22.2; a disintegrin and metalloproteinase 10 （ADAM10） gene was identified as the possible causative gene by exome sequencing; Sanger sequencing showed that a splice-site mutation c.1511+1G>A in the ADAM10 gene was co-segregated with the disease phenotype in the FPH family 1. Immunohistochemical staining demonstrated that ADAM10 was expressed in both the FPH lesions and normal skin tissues of the proband in the FPH family 1. A missense mutation c.1172C＞T （p.Ser319Phe） was identified by further ADAM10 mutation analysis in another 3-generation family with FPH（family 2）. Both the above mutations were not detected in 300 local healthy controls. Conclusion ADAM10 was identified as a novel causative gene responsible for FPH.

Key words: Familial progressive hyperpigmentation, ADAM10, Genetic linkage, Whole exome sequencing