【作者】 周燕；

【导师】 张福仁；

【作者基本信息】 济南大学 ， 皮肤病与性病学， 2013， 硕士

【摘要】 研究背景汗孔角化症(Porokeratosis，PK)是一种角化异常性皮肤病，属常染色体显性遗传，临床主要分为：斑块型(PM)，播散性浅表性汗孔角化症(DSP)，播散性浅表性光化性汗孔角化症(DSAP)，掌跖合并播散性汗孔角化症(PPPD)，线状汗孔角化症(LP)，掌跖点状汗孔角化症(PPPP)。其中播散性浅表性光化性汗孔角化症(DSAP)是最常见的一种类型，好发于30-40岁，男性多见，皮损以中央轻度萎缩，边缘呈嵴状隆起的浅褐色离心性环状斑为特征，主要分布在面、颈、躯干上部、上肢伸侧等曝光部位，日光或紫外光照射可能诱发皮损或使之加重。组织病理学上以鸡眼样层板（即角化不全柱）为特征。到目前为止发现DSAP的四个致病区域，分别定位于12q23.2-24.1(DSAP1),15q25.1-26.1(DSAP2),1p31.3-p31.1(DSAP3),16q24.1-24.3(DSAP4)，且在DSAP1区域发现3个致病基因SSH1，SART3和MVK。本研究收集10个DSAP家系及4个DSAP散发病例，通过DNA直接测序法对SSH1、SART3和MVK基因进行突变分析。目的检测中国汉族播散性浅表性光化性汗孔角化症患者SSH1、SART3、MVK基因突变位点。方法收集整理中国汉族的10个家系及4个散发DSAP患者临床资料及家系情况，并抽取患者、家系成员及100名无亲缘关系健康对照个体血样，提取其外周血DNA，采用聚合酶链反应扩增患者、家系成员和100名无亲缘关系健康对照个体SSH1，SART3，MVK基因的全部外显子编码区及其侧翼序列，通过对PCR扩增产物直接测序进行序列分析，检测上述3个基因突变位点。结果通过对中国汉族人播散性浅表性光化性汗孔角化症（DSAP）患者进行突变检测，在DSAP患者中发现3个国内外未曾报道的MVK基因突变位点（在家系1和家系2患者中发现共同突变c.395delT，在散发病例1和散发病例2中分别发现突变c.853ins A，c.1057delTGGAGGCCACGAAG），而这10个家系中表型正常个体及100个无关正常对照中均不存在这样的突变。SSH1基因、SART3未检测到基因突变位点。结论MVK3个突变位点在中国汉族DSAP患者中均为首次报道，本研究证实该三种突变是引起DSAP临床症状的致病性突变，而不是正常多态性，更值得注意的是在家系2患者与散发病例1身上除有典型的DSAP皮损外还存在典型斑块皮损，提示MVK不仅是DSAP的致病基因，而且与PM的发病可能也有一定的联系，这为研究DSAP患者发病机理及MVK基因与其他类型了汗孔角化症之间的关系提供了新的理论依据，同时为将来的遗传咨询、产前诊断及基因治疗打下了基础。更多还原

【Abstract】 Background: Porokeratosis is a group of hereditary disorders of epidermalkeratinization, characterized by keratotic lesions with an atrophic centre andprominent peripheral ridge, and a typical histological cornoid lamella. There areseveral clinical subtypes of porokeratosis, including disseminated superficial actinicporokeratosis (DSAP), disseminated superficial porokeratosis (DSP), classicporokeratosis of Mibelli (PM), Porokeratosis palmariset plantaris disseminata (PPPD)and Linear porokeratosis(LP), all of whom show typical pathological manifestations:cornoid lamella in the epidermis. Among of them, DSAP as the most commonclinical subtype of porokeratosis, has been widely studied to identify the geneticvariance. Up to date, four genetic loci have been mapped to be responsible for DSAP,12q23.2-24.1(DSAP1),15q25.1-26.1(DSAP2),1p31.3-p31.1(DSAP3), and16q24.1-24.3(DSAP4). SSH1, SART and MVK genes located in DSAP1have beenidentified as the causal genes in Chinese DSAP patients.Objective: Here we performed genetic investigation of ten familial and four sporadicChinese DSAP patients.Methods: Genomic DNA was extracted from the peripheral blood of14affectedindividuals and2unaffected individuals from10DSAP families,4sporadic cases and 100healthy controls. Polymerase chain reaction(PCR) and direct sequencing of theMVK gene were performed to identify and confirm the mutations in the patients.Results: The frameshift mutations of c.395delT(exon5), c.853insA(exon9),c.1057del TGGAGG CCACGAAG (exon11) was identified in Family1, Family2,Sporadic1, Sporadic2, respectively. Among of them, the case of Family1andFamily2have the same mutation (c.395delT).None of these mutations was found inunaffected family members and100controls.Conclusion: Three novel frameshift mutations were found in10DSAP families,4sporadic cases, which further expand the database of MVK mutations in DSAP. It isintriguing that we also detected mutations of MVK gene in two DSAP co-existingwith PM cases, which indicates that PM and DSAP may both result from the mutationof MVK gene. This study should be useful for genetic counseling, prenatal diagnosisand gene therapy for the patients.更多还原