RMND5A基因在遗传性泛发性色素异常症中的致病机理研究

项目名称： RMND5A基因在遗传性泛发性色素异常症中的致病机理研究

项目编号： No.81502714

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 崔红宙

作者单位： 山西医科大学

项目金额： 18万元

中文摘要： 遗传性泛发性色素异常症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。本研究前期收集3例DUH家系和8例散发病例，在1例未携带ABCB6基因突变的DUH家系进行外显子组芯片扫描以及外显子组测序，发现了致病基因RMND5A，在另一例DUH家系中检测到了RMND5A基因的第二种突变。在前期基础上，本研究拟对人培养黑素细胞进行基因转染和siRNA干扰，构建RMND5A-PSGH2重组质粒转染斑马鱼胚胎细胞，通过QRT-PCR、Western-blot及酪氨酸酶活性测定等技术检测成鱼活体内黑素细胞功能变化。利用miR-138 mimics，RMND5A siRNA对人黑色瘤A375细胞进行转染，探讨miR-138-RMND5-Exportin-5通路在黑素细胞功能异常中的作用机制。丰富DUH发病机理认识。同时完善RMND5A基因突变谱，为日后基因诊断打好基础。

中文关键词： 基因突变；遗传性疾病；黑色素细胞；全外显子组测序；汉族人

英文摘要： Dyschromatosis universalis hereditaria (DUH) is an autosomal inherence genodermatosis, characterised by hyperpigmented and hypopigmented macules of the whole body. We have recruited 3 families and 8 sporadic DUH and sent them for mutational analysis in ABCB6 gene. Only one sporadic patient was found carrying ABCB6 muation. We selected one definitely diagnosed DUH family (DUH1) with no ABCB6 mutation for exome genotyping and whole-exome sequencing, one missense mutation in RMND5A gene was identified. By mutational analysis in other patients, one additional missense mutation in RMND5A was found in DUH2 family. The results suggest that RMND5A is a causative gene for DUH. Based on these achievements, the project focuses on undercovering the pathogenic role of RMND5A in DUH. By transfecting RMND5A coding and siRNA into melanocyte, we detected the related gene transcription and functional protein expression in melanocyte maturation and melanin synthesis by QRT-PCR, Western-blot and co-immunoprecipitation technologies. By constructing the transgenic zebrafish with RMND5A-PSGH2 and RMND5A siRNA injection into embryonic cells, we detect functional difference in melanocyte in vivo. By transfecting miR-138 mimics and RMND5A siRNA into human Melanoma A375 cells, we investigate the mechnism of miR-138-RMND5A-Exportin-5 in abnormal function of melanoma cell. This project will improve the cognition of DUH. Meanwhile, we will recruit more DUH cases for the RMND5A gene sequencing and improve the mutation spectrum, which attends to achieve more comprehensive genetic diagnosis.

英文关键词： gene mutation;genetic disease;melanocyte;exome sequencing;Han population