【作者】 任韵清；

【导师】 杨森； 张学军；

【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 毛囊角化病又称Darier病(Darier’s disease，DD)，是一种少见的遗传性角化不良性皮肤病，1889年Darier和White首先报道了该病。男女发病率大致相等，呈常染色体显性遗传模式，人群中患病率1／30，000到1／100，000。临床上以皮脂溢出部位如头皮、前额、耳后、胸背部及四肢弯曲部位等处角化性、脂溢性丘疹为特征，有时可伴有掌跖及指甲的损害。该病多在青春期发病，外显率很高，但临床表型却是多种多样的。轻症病人可仅表现为散在的角化性丘疹或指甲的轻微改变，病情严重时可出现泛发的疣状斑块，并在腋下、腹股沟等处增殖显著，局部浸润，伴恶臭。有报道在一些家系中可以同时患有其他的一些神经、精神性疾患如癫痫、智力发育迟缓等。目前认为该病是由位于12q23-q24.1的ATP2A2基因突变所致。ATP2A2基因编码肌浆网／内质网钙离子ATP酶2(SERCA2)，是一种钙泵，通过水解ATP将细胞内钙离子泵入肌浆网，从而维持细胞浆内低钙离子浓度，在维持细胞内钙离子信号传导中起重要作用。自从该致病基因被发现以来，现在全世界范围内的所有已经报道的不同人群、不同类型的毛囊角化病的基因突变已经达到了140多种，但尚未发现其基因型与表型之间具有一致的相关性。 目的 检测中国毛囊角化病患者存在的ATP2A2基因突变，分析中国人DD的临床特点和突变筛查结果，以期获得更多的基因型和表型的相关信息。 方法 (1)采用PCR反应扩增ATP2A2基因的21个外显子编码区及侧翼序列，用直接测序的方法对3个毛囊角化病家系成员和2个单发病例进行ATP2A2基因的突变检测。(2)通过中国生物医学光盘CBM，对1989年以来在中国报道的毛囊角化病病例进行检索，总结它们的临床特点和突变筛查结果。 结果 (1)在3个DD家系和2个单发病例中共检测出ATP2A2基因的4个新的错义突变和1个重复的剪接部位突变：c．1482G→A(M494I)，c．2299A→G(N767D)，更多还原

【Abstract】 Background Darier’s disease (DD, Darier-White disease, keratosis follicularis; OMIM 124200) is a genetic skin disorder first reported in the year 1889 by Darier and White independently. It is a rare autosomal dominant disease, affecting both sexes and all ethnic groups, with a prevalence ranging from 1/30,000 to 1/100,000. The typical clinical presentation includes keratotic papules predominately in seborrheic areas, (comprising the scalp, forehead, retroauricular folds, upper arms, front and back of the central trunk, and flexures), palmoplantar pits, and distinctive nail abnormalities,with histological acantholysis and dyskeratosis.Onset of Darier’s disease is usually around puberty with complete penetrance but the phenotype is variable. Mild patients may have sparsely scattered keratotic papules or subtle nail changes, whereas severe patients present verrucous plaques or malodorous hypertrophic flexural disease. In a few families, neuropsychiatric abnormalities such as mild mental retardation and epilepsy have been reported. The mutations responsible for DD have been identified in the ATP2A2 gene on chromosome 12q23-24.1. This gene encodes the sarco/endoplasmic reticulum Ca2+ ATPase type 2 isoform (SERCA2), which transports Ca2+ from the cytosol into the endoplasmic reticulum lumen and plays a pivotal role in intracellular calcium signaling. To date, at least 140 mutations in the ATP2A2 gene have been identified as the genetic basis of DD, and no apparent relation between genotype/phenotype has emerged.Objective To confirm the presence of SERCA2 mutations in Chinese DD patients and to get more information for a relationship between genotype and phenotype. Methods (1) All 21 exons including intron-exon boundaries were amplified by polymerase chain reaction (PCR) using published primers, then we sequence the ATP2A2 gene in 3 Chinese Families and 2 Sporadic Patients with DD. (2) We searched更多还原