Lu Weining, van Eerde Albertien M, Fan Xueping, Quintero-Rivera Fabiola, Kulkarni Shashikant, Ferguson Heather, Kim Hyung-Goo, Fan Yanli, Xi Qiongchao, Li Qing-Gang, Sanlaville Damien, Andrews William, Sundaresan Vasi, Bi Weimin, Yan Jiong, Giltay Jacques C, Wijmenga Cisca, de Jong Tom P V M, Feather Sally A, Woolf Adrian S, Rao Yi, Lupski James R, Eccles Michael R, Quade Bradley J, Gusella James F, Morton Cynthia C, Maas Richard L
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Am J Hum Genet. 2007 Apr;80(4):616-32. doi: 10.1086/512735. Epub 2007 Feb 14.
Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.
先天性肾脏和尿路畸形（CAKUT）包括膀胱输尿管反流（VUR）。VUR是一种复杂的、具有遗传异质性的发育障碍，其特征是尿液从膀胱逆行流入输尿管，并与反流性肾病相关，反流性肾病是儿童和年轻成人终末期肾病的15%的病因。我们研究了一名患有新发易位46,X,t(Y;3)(p11;p12)dn的男性，他表现出多种先天性异常，包括严重的双侧VUR伴输尿管膀胱连接部缺陷。这种易位破坏了ROBO2，ROBO2编码一种SLIT配体的跨膜受体，并产生显性负性ROBO2蛋白，在体外消除SLIT-ROBO信号。此外，我们在两个不相关的家族中鉴定出两个与CAKUT和VUR共分离的新型ROBO2细胞内错义变体。Robo2基因剂量减少的成年杂合和嵌合突变小鼠也表现出明显的CAKUT-VUR表型。这些结果共同表明SLIT-ROBO信号通路在一部分人类VUR的发病机制中起作用。
