遗传性泛发性色素异常症致病基因及相关致病机理的研究

Dyschromatosis universalis hereditaria (DUH) is an autosomal inherence genodermatosis,characterised by hyperpigmented and hypopigmented macules of the whole body. We identified that ABCB6 mutation existed in some DUH families, but in other cases the pathogenic gene remains unknown. This research focuses on undercovering the linkage between the gene mutation and clinical phenotype of DUH . The unknown pathogenic gene mutations will be detected in 13 DUH families by linkage analysis and the whole exome sequencing. By constructing melanocyte cell line expressing mutant protein ABCB6p.S322R, through RT - PCR, Western blot and other technicals, we will be able to testing expression level of melanocyte cell differentiation related gene as well as the function protein. By the microporous membrane filter method, tyrosinase activity determination, melanosome content determination, we will be able to test melanocyte function, unrevealing the affection ABCB6 gene mutation has on melanocyte structure, differentiation and cell function . By whole genome microarray, the gene expression differences will be obtained, sheding light on the potential signal path. This research will guide the clinical diagnosis of DUH, enrich our knowledge on pigmentary skin disease, achieve more comprehensive prenatal diagnosis, and provide ideas for early effective disease intervention.

遗传性泛发性色素异常症(DUH)是一种常染色体显性遗传病，皮损表现为泛发全身的色素沉着和色素减退斑。本研究前期验证了DUH家系中存在致病基因ABCB6，但仍有一部分病例致病基因未知。本研究拟对13个未知致病基因的DUH家系的外周血基因组进行连锁分析和全外显子组测序，探索DUH其他致病基因；构建表达ABCB6p.S322R突变蛋白的黑素细胞系，通过RT-PCR、Western blot等技术检测黑素细胞分化和功能相关的靶基因和蛋白的表达水平的改变，通过微孔滤膜法、酪氨酸酶活性测定、黑素含量测定检测黑素细胞功能，探索ABCB6基因突变对黑素细胞结构、分化和细胞功能的影响；利用全基因组表达芯片技术，分析病变皮肤组织和正常皮肤组织的基因表达差异，发现可能导致疾病的信号通路。指导DUH的临床诊断及疾病分型，丰富我们对于色素性疾病发病机理的认识，实现更全面的进行产前诊断，为早期有效的疾病干预提供思路

遗传性泛发性色素异常症(DUH)是一种常染色体显性遗传病，皮损表现为泛发全身的色素沉着和色素减退斑。前期研究发现了DUH的致病基因ABCB6，但仍有一部分病例致病基因未知。本研究拟对13个未知致病基因的DUH家系的外周血基因组进行连锁分析和全外显子组测序，探索DUH其他致病基因。通过基于目标芯片捕获的二代测序技术批量检测临床诊断为DUH的患者的致病基因。通过全外显子组测序，对未检出目标突变的DUH患者进行致病基因的筛查。通过全外显子组测序对一例家族性良性雀斑样痣的家系进行致病基因的检测。设计了遗传性皮肤病基因诊断芯片，并对60余例色素性皮肤病及其他遗传性皮肤病患者的进行了基因诊断。指导DUH的临床诊断及疾病分型，丰富我们对于色素性疾病及遗传性皮肤病发病机理的认识，实现更全面的进行产前诊断，为早期有效的疾病干预提供思路。

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