遗传性对称性色素异常症一家系分析

发布时间：2018-02-21 21:34

本文关键词： 遗传性对称性色素异常症 ADAR基因突变　出处：《中国医科大学》2010年硕士论文　论文类型：学位论文

【摘要】： 研究背景遗传性对称性色素异常症(Dyschromatosis Symmetrica Hereditaria,, DSH; OMIM 127400)又称Dohi对称性肢端色素沉着,是一种少见的常染色体显性遗传性皮肤病。该病最先由日本学者Toyama于1910年描述,并于1929年正式提出命名。DSH的典型表现为肢端对称分布的色素沉着斑和色素减退斑,尤以手背和足背部位最为明显,亦可延及前臂及小腿,呈网状。部分患者面部可见雀斑样色素沉着,一般无自觉症状。2003年日本学者Miyamura等发现ADAR基因是本病的致病基因,位于1q21.3约500kb关键区域。遗传性泛发性色素异常症(Dyschromatosis Universalis Hereditaria,, DUH; OMIM 127500)是一种少见的常染色体显性遗传性皮肤病,皮损主要表现为全身泛发性色素沉着斑和色素减退斑。早期研究认为,遗传性对称性色素异常症是该病的一种亚型,近年随着对致病基因的深入研究,发现遗传性对称性色素异常症和遗传性泛发性色素异常症是两类不同的疾病。屈侧网状色素沉着症(Reticular pigmented anomaly of the flexures, RPAF; OMIM 179850)又称Dowling-Degos病(Dowling-Degos disease, DDD),是一种少见的常染色体显性遗传性皮肤病。其临床特征是对称性的褐色斑疹,渐扩展融合成网状,好发在腹股沟、股内侧、腋下、腕、颈等屈侧部位,多于青春期发病。DSH、DUH与DDD在临床表现及病理改变上有许多相似之处,基因学诊断是鉴别的主要方法。目的 1、寻找家系ADAR基因突变位点； 2、对疑似患者进行基因学诊断。方法 1、整理家系资料,分析临床表型； 2、针对DSH、DUH、DDD选择STR markers,对家系进行连锁分析； 3、采用PCR反应扩增ADAR基因的15个外显子编码区及侧翼序列,用直接测序的方法对所有病例进行ADAR基因的突变检测。结果 1、家系四代随代数增加,由典型表现(手背、足背、肘、膝等部位网状色素沉着与减退的网状斑)演变为仅在面部出现的雀斑样痣,临床表现有明显渐轻趋势；部分患者出现唇周改变,在以往文献中未曾报道。 2、测序回报在ADAR基因的15个外显子编码区及侧翼序列中未发现突变基因。 3、在染色体1q22的微卫星标记(chr1：154528835-154528881)处确定连锁,排除了致病基因与染色体6q24.2-q25.2,12q21-q22,12q13的定位区域连锁。 4、疑似患者在确定连锁的位点无共享条带,从而除外DSH。结论 1、发现该家系病例随代数增加,其临床症状有减轻趋势；部分患者有未曾报道的临床表现； 2、在距DSH致病基因ADAR 5000kb处确定连锁；排除了DUH、DDD的可能; 3、排除疑似患者患病的可能； 4、该家系病例ADAR基因的15个外显子编码区及侧翼序列未见异常,提示致病基因可能位于内含子区域、5’端的启动子区域或者ADAR附近的其它基因,有待下一步继续研究。
[Abstract]:Research background. Dyschromatosis Symmetrica (DSH; OMIM 127400), also known as Dohi symmetric acropigmentation, is a rare autosomal dominant hereditary dermatosis. The disease was first described by Japanese scholar Toyama in 1910. In 1929, it was formally proposed that the typical expression of .DSH is pigmentation spots and hypopigmentation spots distributed symmetrically at the extremities, especially in the back of the hand and the dorsal part of the foot, and also in the forearm and the lower leg. In 2003, Japanese scholar Miyamura and others found that ADAR gene was the pathogenic gene of the disease. Dyschromatosis Universalis Hereditariaanus (DUH; OMIM 127500) is a rare autosomal dominant hereditary dermatosis, which is mainly characterized by systemic generalized pigmentation and hypopigmentation. Hereditary symmetrical dystrophy is a subtype of the disease. In recent years, with the in-depth study of pathogenic genes, It has been found that hereditary symmetrical dystrophy and hereditary generalized dyskinesia are two different diseases. Flexular pigmented anomaly of the flexures (RPAF; OMIM 179850), also known as Dowling-Degos disease Dowling-Degos disease, is a rare autosomal disease. Sexual hereditary dermatosis. Its clinical features are symmetrical brown macules, It is more common in inguinal, medial femoral, armpit, wrist, neck and equal flexion than puberty. DUH and DDD have many similarities in clinical manifestations and pathological changes. Genetic diagnosis is the main method to differentiate. Purpose. 1. To find the mutation site of ADAR gene in families; 2. Genetic diagnosis of suspected patients. Method. 1. Sorting out the family data and analyzing the clinical phenotype; (2) STR markers were selected for DUHD-DDD, and linkage analysis was carried out on the families. 3. The 15 exon coding regions and flanking sequences of ADAR gene were amplified by PCR reaction, and the mutation of ADAR gene was detected by direct sequencing in all cases. Results. 1. The four generations of pedigree increased with algebra, from typical manifestations (reticular pigmentation and decreased reticular plaques on the back of hand, back of foot, elbow, knee, etc.) to freckle nevus, which appeared only on the face. Some patients had perilabial changes, which had not been reported in previous literature. 2. No mutant gene was found in 15 exon coding regions and flanking sequences of ADAR gene by sequencing. 3. The linkage was confirmed at the microsatellite marker chr1: 154528835-154528881 of chromosome 1q22, which excluded the linkage between the pathogenic gene and the locational region of chromosome 6q24.2-q25.2C12q21-q2212q13. 4. The suspected patients had no shared bands at the identified linkage sites, with the exception of DSHs. Conclusion. 1. It was found that the clinical symptoms of the family increased with the increase of algebra, and some of the patients had unreported clinical symptoms. (2) the linkage was confirmed at 5000kb from the DSH pathogenic gene ADAR, and the possibility of DUHD-DDD was excluded. (3) to rule out the possibility of suspected patient becoming ill; 4. The 15 exon coding regions and flanking sequences of ADAR gene were not abnormal, suggesting that the pathogenic gene might be located in the promoter region of intron region 5'or other genes near ADAR.
【学位授予单位】：中国医科大学
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：R758.5

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