【作者】 朱亚刚；

【导师】 张学军； 杨森；

【作者基本信息】 安徽医科大学 ， 皮肤病与性病学， 2006， 硕士

【摘要】 研究背景：家族性慢性良性天疱疮，又称Hailey-Hailey病(HHD，OMIM 169600)是一种罕见的常染色体显性遗传性皮肤病。临床上以皮肤皱褶部位反复出现水疱和糜烂为特征。该病由Hailey兄弟于1939年首次报道，大部分患者在三四十岁左右发病，皮损主要位于颈部、腋窝、腹股沟等皱褶部位，黏膜受累很少见，但口腔、食管黏膜、外阴部位也可见到损害。有些患者的手指甲可见到无症状的纵向白线，在疾病的诊断过程中具有提示性作用。出汗、摩擦、皮肤感染等一些外界因素会诱发疾病的发病或加重病情。组织病理检查显示基层上水疱形成和许多棘刺松解细胞，基底细胞如倒砖墙样外观。超微结构研究显示已从桥粒附着板缩回的角蛋白中间微丝聚集在核周。连锁分析将HHD致病基因定位于染色体3q21-q24，最新研究显示ATP2C1基因突变导致该疾病的发生，ATP2C1基因编码人类分泌型钙离子ATP酶1。自从报道ATP2C1基因为致病基因以来，一系列错义突变、框移突变、剪切位点改变和无义突变被发现。基因型与表型的关联研究并没有发现基因突变位点与HHD的疾病表型之间存在相关性。在此研究中，我们收集了两个中国汉族人HHD家系，并通过直接测序的方法对这两个家系成员进行了ATP2C1基因的突变检测。目的：检测这两个中国汉族人HHD家系的ATP2C1基因的致病性突变。方法：我们收集了两个中国汉族人HHD家系及其家庭成员的外周血标本，利用基因组DNA抽提试剂盒抽提外周血白细胞中的DNA，设计覆盖ATP2C1基因所有外显子编码区的二十六对引物，采用PCR反应扩增所有外显子编码区及其侧翼序列，通过对PCR反应产物直接测序进行序列分析。结果：发现两个新的杂合性突变，包括一个无义突变(p.G633X)和一个框移突变(c.2164insACAT)，这两个突变在相对应的家系患者中都存在，而在正常个体及一百个无关正常对照中不存在这样的突变，证明了这两个突变是致病性突变而非正常多态性。结论：我们的研究结果更多还原

【Abstract】 Background Familial benign chronic pemphigus or Hailey-Hailey disease (HHD; OMIM 169600) is a rare autosomal dominant cutaneous disorder characterized by recurrent vesicles and erosions mainly in intertriginous areas. It was first described by the brothers Hailey in 1939. The disease usually presents in the third or fourth decade and the lesions occur mainly on the neck and intertriginous areas; mucosal involvement is rare, but has been seen in the mouth, esophagus, and vulva. Asymptomatic longitudinal white lines on the fingernails are seen in some patients. Lesions are induced or exacerbated by external factors such as sweating, friction, and cutaneous infection. Histologic examination shows numerous acantholytic cells and the suprabasal type of blister formation, ultrastructural studies of acantholytic cells in HHD reveal perinuclear aggregates of keratin intermediate filaments that have retracted from desmosomal plaques. Linkage analysis mapped the gene responsible for HHD to chromosome 3q21-q24. Recent studies have revealed that HHD is caused by mutations in the ATP2C1 gene encoding the human secretory pathway calcium ATPase1(hSPCA1). A spectrum of missense, frameshift, splice-site, and nonsense mutations have since been reported in ATP2C1. Comparison between genotype and phenotype failed to yield any clear correlation between the nature of the mutation and the clinical features of HHD. In the present study, we have ascertained two Chinese families with HHD, and examined ATP2C1 gene mutations in these two families by direct sequencing. Objectives To identify pathogenic mutations of the ATP2C1 gene in two Chinese更多还原