LGR4/GPR48 Inactivation Leads to Aniridia-Genitourinary Anomalies-Mental Retardation Syndrome Defects
LGR4/GPR48 Inactivation Leads to Aniridia-Genitourinary Anomalies-Mental Retardation Syndrome Defects
复制标题
DOI：
10.1074/jbc.m113.530816
复制
发表时间：
2014-03-28
影响因子：
4.8
通讯作者：
Liu, Mingyao
中科院分区：
文献类型：
--
作者：
Yi, Tingfang;Weng, Jinsheng;Liu, Mingyao
背景：无虹膜-泌尿生殖系统异常-智力低下(AGR)综合征的发病机制尚不清楚。结果：LGR4基因缺失可导致小鼠无虹膜、多囊肾病、泌尿生殖系统异常和智力低下，类似于AGR综合征的病理缺陷。结论：LGR4基因是AGR综合征发病的候选基因。意义：了解AGR综合征的发病机制AGR综合征(无虹膜、泌尿生殖系统异常和智力低下的临床三联症，肾母细胞瘤、无虹膜、泌尿生殖系统异常和智力发育迟缓的WAGR综合征的一个亚型)是一种罕见的综合征，由11p13-14区域的连续基因缺失引起。然而，WAGR综合征的发病机制尚不清楚。在本研究中，我们证明了人类染色体11p12-11p14.4片段中唯一的G蛋白偶联受体基因LGR4(又称GPR48)是AGR综合征发病的关键基因。小鼠LGR4基因缺失导致无虹膜、多囊肾病、泌尿生殖系统异常和智力低下，类似于AGR综合征的病理缺陷。此外，LGR4失活显著增加了细胞凋亡，降低了参与WAGR综合征相关器官发育的多个重要基因的表达。具体地说，LGR4的缺失通过cAMP-CREB信号通路下调了组蛋白去甲基酶Jmjd2a和Fbxl10在小鼠胚胎成纤维细胞以及在泌尿和生殖系统小鼠组织中的表达。我们的数据表明，LGR4基因通过遗传和表观遗传学监测来调节眼、肾、睾丸、卵巢和子宫器官的发育以及智力发育，是AGR综合征发病机制的一个新的候选基因。
Background: The pathogenic mechanisms of aniridia-genitourinary anomalies-mental retardation (AGR) syndrome are obscure. Results: Depletion of Lgr4 in mouse leads to aniridia, polycystic kidney disease, genitourinary anomalies, and mental retardation, similar to the pathological defects of AGR syndrome. Conclusion: Lgr4 is a candidate gene for the pathogenesis of AGR syndrome. Significance: Understanding the mechanisms of the pathogenesis of AGR syndrome.AGR syndrome (the clinical triad of aniridia, genitourinary anomalies, and mental retardation, a subgroup of WAGR syndrome for Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation) is a rare syndrome caused by a contiguous gene deletion in the 11p13-14 region. However, the mechanisms of WAGR syndrome pathogenesis are elusive. In this study we provide evidence that LGR4 (also named GPR48), the only G-protein-coupled receptor gene in the human chromosome 11p12-11p14.4 fragment, is the key gene responsible for the diseases of AGR syndrome. Deletion of Lgr4 in mouse led to aniridia, polycystic kidney disease, genitourinary anomalies, and mental retardation, similar to the pathological defects of AGR syndrome. Furthermore, Lgr4 inactivation significantly increased cell apoptosis and decreased the expression of multiple important genes involved in the development of WAGR syndrome related organs. Specifically, deletion of Lgr4 down-regulated the expression of histone demethylases Jmjd2a and Fbxl10 through cAMP-CREB signaling pathways both in mouse embryonic fibroblast cells and in urinary and reproductive system mouse tissues. Our data suggest that Lgr4, which regulates eye, kidney, testis, ovary, and uterine organ development as well as mental development through genetic and epigenetic surveillance, is a novel candidate gene for the pathogenesis of AGR syndrome.