表皮松解性角化过度型鱼鳞病一家系KRT10基因突变的研究及应用维甲酸治疗的临床观察
发布时间：2018-11-26 17:22
【摘要】： 前言 鱼鳞病(ichthyosis)是一组以皮肤干燥伴片层鱼鳞状粘着性鳞屑为特征的角化异常性遗传性皮肤病。根据遗传机制、临床表现及组织病理学的差异,主要分为四型：寻常型鱼鳞病(ichthyosis vulgaris, IV )、表皮松解性角化过度型鱼鳞病(epidermolytic hyperkeratosis, EHK)、X连锁型鱼鳞病(X-linked ichthyosis,XLI)、先天性非大疱性鱼鳞病样红皮病(nonbullous congenital ichthyosiform erythroderma, NCIE)。表皮松解性角化过度型鱼鳞病(EHK)是一种罕见的常染色体显性遗传性皮肤病(MIM 113800),其发生率在0.33／10万～1／10万之间。约有半数病人有阳性家族史,90%的患者在1岁时开始有皮肤损害,71%出生时就有。本病具有很高的自发突变率,至少半数病例为散发性。遗传学的连锁分析、基因突变和转基因小鼠研究,都表明EHK是由编码基底层以上的角蛋白基因1(KRT1)和10(KRT10)突变引起的。本研究利用直接测序的方法对该家系进行KRT1和KRT10基因的所有编码区,特别是热点区基因突变的检测,以期发现新的致病突变,进一步丰富基因的突变谱。 材料和方法 一、实验材料 (一)研究对象： 经中国医科大学附属第一医院皮肤科确诊的辽宁汉族表皮松解性角化过度型鱼鳞病一家系,其中二人发病,为母子关系,且其临床表现相同。 (二)主要试剂： 10%SDS、EDTA、硼酸、蛋白酶K、Tris饱和酚、氯仿、无水乙醇、溴化乙啶、琼脂糖、TBE缓冲液、2×Taq plus PCR Master Mix。 二、实验方法 取患者皮损进行组织病理检查,提取该家系成员的外周血DNA,采用聚合酶连反应(PCR)及DNA直接测序方法,检测患者角蛋1(KRT1)及角蛋白10(KRT10)的基因突变。确诊之日起予先证者第三代维甲酸(阿罗神)口服,同时配合外用药治疗。 结果 该家系2例患者存在KRT10基因的杂合点突变,即在KRT10基因第2140位G→A,导致其第156位的精氨酸变为组氨酸(R156H)。维甲酸治疗四个月后,症状改善,皮肤鳞屑明显变薄。 结论 KRT10R156H是导致该家系2例患者临床表型的特异突变,进一步证实KRT10基因第156位密码子是突变热点,从而为基因诊断和基因治疗提供一定的依据。维甲酸治疗效果显著。
[Abstract]:Preface ichthyosis (ichthyosis) is a group of keratosis hereditary skin diseases characterized by dry skin and lamellar scales. According to the genetic mechanism, clinical manifestations and histopathological differences, there are mainly four types: (ichthyosis vulgaris, IV), 's epidermolytic hyperkeratosis, (epidermolytic hyperkeratosis, EHK), X linked ichthyosis (X-linked ichthyosis,XLI). Congenital non-bullous ichthyosis (nonbullous congenital ichthyosiform erythroderma, NCIE). Epidermolytic hyperkeratosis (EHK) is a rare autosomal dominant hereditary dermatosis (MIM 113800) with an incidence of 0.33% ~ 1 / 100 000. About half of the patients had a positive family history, 90 per cent had skin damage at age 1 and 71 per cent were born with skin damage. The disease has a high spontaneous mutation rate, at least half of the cases are sporadic. Genetic linkage analysis, gene mutation and transgenic mouse studies showed that EHK was caused by keratin 1 (KRT1) and 10 (KRT10) mutations above the basal layer. In this study, direct sequencing was used to detect all the coding regions of KRT1 and KRT10 genes, especially the mutations in hot spots, in order to find new pathogenic mutations and further enrich the mutation profiles of the genes. Materials and methods 1. Experimental materials (1) subjects: a family of epidermolysis hyperkeratosis in Liaoning Han nationality was confirmed by the dermatology department of the first affiliated Hospital of China Medical University. Two of them had a maternal-child relationship, and their clinical manifestations were the same. (II) main reagents: SDS-EDTA, boric acid, proteinase KTIs saturated phenol, chloroform, anhydrous ethanol, ethidium bromide, agarose, TBE buffer, 2 脳 Taq plus PCR Master Mix. Secondly, the skin lesions of the patients were taken for histopathological examination. The peripheral blood DNA, of the family members was extracted by polymerase chain reaction (PCR) and DNA direct sequencing. The gene mutations of keratin 1 (KRT1) and keratin 10 (KRT10) were detected. From the date of diagnosis, the third generation of retinoic acid (aroshen) was given orally and treated with foreign medicine. Results the heterozygous point mutation of KRT10 gene was found in two patients of this family, that is, the 2140 G of KRT10 gene resulted in the transformation of the 156th arginine into histidine (R156H). After four months of retinoic acid treatment, symptoms improved and skin scales thinned significantly. Conclusion KRT10R156H is a specific mutation leading to the clinical phenotype of 2 patients in this pedigree. It is further confirmed that codon 156 of KRT10 gene is a hot spot of mutation, which provides a basis for gene diagnosis and gene therapy. The therapeutic effect of retinoic acid is remarkable.
【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】：R758.52
[Abstract]:Preface ichthyosis (ichthyosis) is a group of keratosis hereditary skin diseases characterized by dry skin and lamellar scales. According to the genetic mechanism, clinical manifestations and histopathological differences, there are mainly four types: (ichthyosis vulgaris, IV), 's epidermolytic hyperkeratosis, (epidermolytic hyperkeratosis, EHK), X linked ichthyosis (X-linked ichthyosis,XLI). Congenital non-bullous ichthyosis (nonbullous congenital ichthyosiform erythroderma, NCIE). Epidermolytic hyperkeratosis (EHK) is a rare autosomal dominant hereditary dermatosis (MIM 113800) with an incidence of 0.33% ~ 1 / 100 000. About half of the patients had a positive family history, 90 per cent had skin damage at age 1 and 71 per cent were born with skin damage. The disease has a high spontaneous mutation rate, at least half of the cases are sporadic. Genetic linkage analysis, gene mutation and transgenic mouse studies showed that EHK was caused by keratin 1 (KRT1) and 10 (KRT10) mutations above the basal layer. In this study, direct sequencing was used to detect all the coding regions of KRT1 and KRT10 genes, especially the mutations in hot spots, in order to find new pathogenic mutations and further enrich the mutation profiles of the genes. Materials and methods 1. Experimental materials (1) subjects: a family of epidermolysis hyperkeratosis in Liaoning Han nationality was confirmed by the dermatology department of the first affiliated Hospital of China Medical University. Two of them had a maternal-child relationship, and their clinical manifestations were the same. (II) main reagents: SDS-EDTA, boric acid, proteinase KTIs saturated phenol, chloroform, anhydrous ethanol, ethidium bromide, agarose, TBE buffer, 2 脳 Taq plus PCR Master Mix. Secondly, the skin lesions of the patients were taken for histopathological examination. The peripheral blood DNA, of the family members was extracted by polymerase chain reaction (PCR) and DNA direct sequencing. The gene mutations of keratin 1 (KRT1) and keratin 10 (KRT10) were detected. From the date of diagnosis, the third generation of retinoic acid (aroshen) was given orally and treated with foreign medicine. Results the heterozygous point mutation of KRT10 gene was found in two patients of this family, that is, the 2140 G of KRT10 gene resulted in the transformation of the 156th arginine into histidine (R156H). After four months of retinoic acid treatment, symptoms improved and skin scales thinned significantly. Conclusion KRT10R156H is a specific mutation leading to the clinical phenotype of 2 patients in this pedigree. It is further confirmed that codon 156 of KRT10 gene is a hot spot of mutation, which provides a basis for gene diagnosis and gene therapy. The therapeutic effect of retinoic acid is remarkable.
【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】：R758.52
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