遗传性对称性色素异常症致病基因突变研究
发布时间：2018-12-25 13:26
【摘要】：遗传性对称性色素异常症(Dyschromatosis symmetrica hereditaria, DSH, OMIM127400)亦称为土肥肢端色素沉着症(acropigmentation of Dohi),是一种较为少见的遗传性皮肤病。该病的主要临床表现为肢端对称分布的色素沉着斑与色素减退斑,尤以手背和足背最为明显,面部可有雀斑样损害,日晒后皮损加重。严重者可累及四肢及全身,一般无自觉症状。通常在婴儿期或者儿童期发病,青春期加重。电镜上表现为黑素细胞数目的减少,在色素沉着区的黑素细胞出现代偿性代谢水平的升高。本病通常表现为常染色体显性遗传,且有较高的外显率。我国学者张学军等已将本病的致病基因定位在1q11-1q21上,日本学者发现DSH致病基因为双链RNA特异性腺苷脱氨酶(DSRAD)基因。我们对4个DSH家系采用PCR和直接测序方法进行突变检测,以期发现DSRAD基因新突变,扩大该基因的突变谱。 目的检测遗传性对称性色素异常症4个家系DSRAD基因的突变,扩大该病的基因突变谱。 方法收集遗传性对称性色素异常症4个家系的外周血标本,采用PCR方法结合DNA直接测序的方法,检测了4个家系成员中共13例患者及7例表型正常者和100例无亲缘关系健康个体的DSRAD基因突变情况。 结果在家系A的所有患者中均检测到DSRAD基因第11号外显子的错义突变c.3,002GT(p. R1001L),第3002位碱基由G突变为T,导致第1001位密码子精氨酸被亮氨酸取代。RT-PCR证实了这一突变。同时发现一个新的SNP：c.2496+30delT(IVS 7+30delT)。在家系B的患者中检测到DSRAD基因第12号外显子上一个新的移码突变c.3089-3090delGA(p. R1030sX1036)。第3089-3090位的两个碱基GA缺失导致移码及过早的终止密码子的产生。家系C中患者DSRAD基因12号外显子第3159位碱基G缺失,即c.3159de1G,导致一新的移码突变p.L1053fs→1076X；家系D中患者DSRAD基因13号外显子第3209位和3210位碱基之间插入1个碱基C(c.3209insC),导致又一新的移码突变p.L1070fs→1092X。 结论4个DSH家系患者均存在DSRAD基因新突变,可能由此引起编码蛋白的结构和功能的改变,致皮肤色素异常。
[Abstract]:Hereditary symmetrical pigmentation (Dyschromatosis symmetrica hereditaria, DSH, OMIM127400), also known as (acropigmentation of Dohi), is a rare hereditary skin disease. The main clinical manifestations of the disease were pigmentation spots and hypopigmentation spots distributed symmetrically on the extremities, especially on the back of the hand and the back of the foot. Severe can involve limbs and the whole body, generally without conscious symptoms. Usually in infancy or childhood, puberty is aggravated. Electron microscopy showed that the number of melanocytes decreased and the modern metabolic level of melanocytes in pigmented areas increased. The disease is usually autosomal dominant and has a high rate of exophthalmos. Zhang Xuejun, a Chinese scholar, has mapped the pathogenicity gene of the disease on 1q11-1q21. Japanese researchers have found that the DSH gene is a double-stranded RNA specific adenosine deaminase (DSRAD) gene. Four DSH families were detected by PCR and direct sequencing in order to find new mutations of DSRAD gene and expand the mutation profile of DSRAD gene. Objective to detect the mutation of DSRAD gene in 4 families with hereditary symmetrical dystrophy and to expand the gene mutation spectrum of the disease. Methods Peripheral blood samples were collected from 4 families with hereditary symmetrical dystrophy. PCR method combined with direct sequencing of DNA was used. DSRAD gene mutations in 13 patients, 7 normal phenotypes and 100 unrelated healthy individuals from 4 families were detected. Results the missense mutation c.3002GT (p.) of exon 11 of DSRAD gene was detected in all patients of family A. R1001L), where the 3002 base group mutated from G to T, leading to the substitution of arginine at codon 1001 by leucine. This mutation was confirmed by RT-PCR. A new SNP:c.2496 30delT (IVS 7 30delT) was also found. A new frameshift mutation c.3089-3090delGA on exon 12 of DSRAD gene was detected in patients with line B at home. R1030sX1036) The deletion of two bases GA at position 3089-3090 leads to the generation of frameshift and premature termination codon. In pedigree C, the deletion of the 3159 base G of exon 12 of the DSRAD gene, namely c. 3159de1G, led to a new frameshift mutation p.L1053fs 1076X. In family D, one base C (c.3209insC) was inserted between exon 3209 and 3210 of DSRAD gene, which led to a new frameshift mutation p.L1070fs 1092X. Conclusion there is a new mutation of DSRAD gene in 4 DSH families, which may lead to the change of the structure and function of the encoded protein and the abnormality of skin pigmentation.
【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R758.54
本文编号：2391191
[Abstract]:Hereditary symmetrical pigmentation (Dyschromatosis symmetrica hereditaria, DSH, OMIM127400), also known as (acropigmentation of Dohi), is a rare hereditary skin disease. The main clinical manifestations of the disease were pigmentation spots and hypopigmentation spots distributed symmetrically on the extremities, especially on the back of the hand and the back of the foot. Severe can involve limbs and the whole body, generally without conscious symptoms. Usually in infancy or childhood, puberty is aggravated. Electron microscopy showed that the number of melanocytes decreased and the modern metabolic level of melanocytes in pigmented areas increased. The disease is usually autosomal dominant and has a high rate of exophthalmos. Zhang Xuejun, a Chinese scholar, has mapped the pathogenicity gene of the disease on 1q11-1q21. Japanese researchers have found that the DSH gene is a double-stranded RNA specific adenosine deaminase (DSRAD) gene. Four DSH families were detected by PCR and direct sequencing in order to find new mutations of DSRAD gene and expand the mutation profile of DSRAD gene. Objective to detect the mutation of DSRAD gene in 4 families with hereditary symmetrical dystrophy and to expand the gene mutation spectrum of the disease. Methods Peripheral blood samples were collected from 4 families with hereditary symmetrical dystrophy. PCR method combined with direct sequencing of DNA was used. DSRAD gene mutations in 13 patients, 7 normal phenotypes and 100 unrelated healthy individuals from 4 families were detected. Results the missense mutation c.3002GT (p.) of exon 11 of DSRAD gene was detected in all patients of family A. R1001L), where the 3002 base group mutated from G to T, leading to the substitution of arginine at codon 1001 by leucine. This mutation was confirmed by RT-PCR. A new SNP:c.2496 30delT (IVS 7 30delT) was also found. A new frameshift mutation c.3089-3090delGA on exon 12 of DSRAD gene was detected in patients with line B at home. R1030sX1036) The deletion of two bases GA at position 3089-3090 leads to the generation of frameshift and premature termination codon. In pedigree C, the deletion of the 3159 base G of exon 12 of the DSRAD gene, namely c. 3159de1G, led to a new frameshift mutation p.L1053fs 1076X. In family D, one base C (c.3209insC) was inserted between exon 3209 and 3210 of DSRAD gene, which led to a new frameshift mutation p.L1070fs 1092X. Conclusion there is a new mutation of DSRAD gene in 4 DSH families, which may lead to the change of the structure and function of the encoded protein and the abnormality of skin pigmentation.
【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R758.54
【参考文献】
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1 张福仁;刘红;蒋德科;田洪青;余龙;;遗传性对称性色素异常症2例基因诊断[J];临床皮肤科杂志;2008年05期
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