Ⅲ型家族性噬血细胞性淋巴组织细胞增生症易感基因UNC13D参与同源重组修复  

Type Ⅲ Familial Hemophagocytic Lymphohistiocytosis Susceptibility Gene UNC13DInvolves in Homologous Recombination Repair

作　　者：常丽贤 曾慧敏 周全全 高敏[2] 魏蔚 周剑峰 安文彬 袁卫平 竺晓凡 

机构地区：[1]中国医学科学院、北京协和医学院血液学研究所、血液病医院,天津300020 [2]中国科学院北京基因组学研究所、重大疾病基因组与个体化医疗实验室、北京100029

出　　处：《中国实验血液学杂志》2013年第3期692-695,共4页Journal of Experimental Hematology

基　　金：国家重大科学研究计划资助(编号2012CB966603);2010-2012卫生部部属(管)医院学科重点项目;国家自然科学基金面上项目(编号81170470);天津国际合作项目(编号09ZCZDSF03800);科技部国际合作(中瑞国际:2010DFB30 270)

摘　　要：本研究从DNA双链断裂同源重组修复角度探讨UNC13D(秀丽新小杆线虫)基因参与Ⅲ型家族性噬血细胞性淋巴组织细胞增生症(familial hemophagocytic lymphohistiocytosis type 3,FHL3)的发病机制。利用DNA同源重组修复方法,检测正常对照组及UNC13D基因下调后DR-U2OS细胞同源重组修复率的变化情况,并研究此基因的相关功能。结果表明:下调DR-U2OS细胞的UNC13D基因表达后,同源重组修复率较正常对照组明显下降,且差异有统计学意义(P<0.05),提示UNC13D编码蛋白Munc13-4不仅参与到细胞毒颗粒的胞吐过程中,而且在DNA双链断裂修复中也起作用。结论:UNC13D基因突变可能通过抑制细胞毒颗粒的胞吐和降低DNA双链断裂后的同源重组修复率参与FHL3发病过程,这一研究结果为揭示FHL3的发病机制提供新的理论基础。This study was aimed to explore the pathogenesis of type familial hemophagocytic lymphohistiocytosis （FHL3） via susceptibility gene UNC13D involving in homologous recombination repair （HRR） of DNA double-strand break （DSB）. By means of DNA homologous recombination repair, the change of homologous recombination repair rate of normal control cells and DR-U2OS cells after down-regulation of UNCBD was detected; the UNCBD gene related function was explored. The results showed that DR-U2OS cells displayed a significant reduction in homologous recombination repair of DNA DSB after siRNA knockdown of UNC13D, compared to its normal control cell counterparts （P 〈 0. 05 ）, suggesting that UNC13D was involved in DNA double-stranded breakage repair. It is concluded that UNC13D gene mutation may be involved in the pathogenesis of FHL3 via its dual effects of both the cytotoxic granule exocytosis and decrease of homologous recombination repair rate after the DNA double-strand break, therefore, providing a new theoretical basis to reveal the oathozenesis of FHL3.

关 键 词：Ⅲ型家族性噬血细胞性淋巴组织细胞增生症 UNC13D基因 DNA双链断裂 同源重组修复 

分 类 号：R551.2[医药卫生—血液循环系统疾病]