SASH1基因新杂合错义突变与遗传性泛发性色素异常症一家系相关

A novel heterozygous missense mutation in the SASH1 gene is associated with dyschromatosis universalis hereditaria in a pedigree

目的探讨一家系遗传性泛发性色素异常症的临床特征和分子遗传学发病基础。方法对该家系进行详细的遗传学调查、体检，并对先证者进行反射式共聚焦显微镜检查和组织病理学检查。采集8例家系成员（其中患者5例，正常个体3例）和200例家系外无亲缘关系的健康对照的血样，提取基因组DNA，PCR扩增SASH1和ABCB6基因的全部外显子及其侧翼序列，并进行DNA直接测序。结果该家系符合常染色体显性遗传模式。家系中9例患者均在出生后1年内发病，皮损最初累及面部，后逐渐泛发于全身。健在的8例患者中，7例皮损表现为不规则淡褐色至深褐色色素沉着斑，其余皮肤呈均匀的色素减退。仅先证者大姐皮损表现为泛发性网状色素沉着斑和色素减退斑。患者的口腔黏膜、指（趾）甲、牙齿和一般健康状况均正常。DNA测序显示，5例患者SASH1基因第15号外显子上均出现1个杂合错义突变（c．1761C〉G，p．Ser587Arg），而家系中3例正常个体及家系外200例健康对照均未检测到此突变。此外，均未发现ABCB6基因突变。结论遗传性泛发性色素异常症的临床特征和分子遗传学发病基础存在异质性。SASH1基因的p．587R突变可能是该家系患者发病的原因。

Objective To investigate clinical features and molecular genetic basis of dyschromatosis universalis hereditaria （DUH） in a pedigree. Methods A detailed genetic survey and a physical examination were performed for available members in a pedigree with DUH. In addition, reflectance confocal microscopy and histopathology were carried out to observe skin lesions of the proband. Blood samples were collected from 8 family members （including 5 patients with DUH and 3 unaffected members） and 200 unrelated healthy human controls. The FlexiGene DNA kit was used to extract genomic DNA from these blood samples, and PCR was performed to amplify all coding exons and their flanking sequences of SASH 1 and ABCB6 genes followed by direct DNA sequencing. Results DUH was inherited in an autosomal dominant manner in this pedigree, and occurred within 1 year after birth in 9 patients. Lesions initially appeared on the face, then gradually spread to the whole body. Among 8 surviving patients, 7 presented with irregularly shaped light brown to puce macules complicated by uniform hypopigmentation of the remaining skin, and only the elder sister of the proband showed generalized hyperpigmented macules mingled with hypopigmented macnles in a reticular pattern. No abnormality was observed in oral mucosa, nails or teeth, and general status was good in the 8 patients. DNA sequencing revealed a novel heterozygous missense mutation （c.1761C 〉 G, p.Ser587Arg） in exon 15 of the SASH1 gene in the 5 available patients, but not in the 3 unaffected individuals or 200 healthy controls. No mutation was found in the ABCB6 gene in any of the 8 family members. Conclusions Heterogeneity exists in clinical features and molecular genetic basis of DUH. The heterozygous missense mutation p.S587R in the SASH1 gene might be responsible for DUH in this family.