Jenkins Dagan, Bitner-Glindzicz Maria, Malcolm Sue, Allison Jennifer, de Bruyn Rose, Flanagan Sarah, Thomas David F M, Belk Rachel A, Feather Sally A, Bingham Coralie, Southgate Jennifer, Woolf Adrian S
Nephro-Urology Unit, UCL Institute of Child Health, London, WCIN IEH, UK.
Nephrol Dial Transplant. 2006 Dec;21(12):3415-21. doi: 10.1093/ndt/gfl465. Epub 2006 Sep 29.
Uroplakin (UP) proteins cover urothelial apical surfaces. Mice lacking UPIIIa have elevated urothelial permeability and congenital renal tract anomalies, and UPIIIa mutations have been reported in children with kidney and ureter malformations. Mice with null mutation of another UP family member, UPII, are often born with congenital hydronephrosis. We hypothesized that UPII mutations may be present in humans with renal tract malformations.
Mutations were sought, using direct sequencing of the five UPII exons, in 42 children with diverse renal tract anomalies.
No UPII abnormalities were detected in 41 patients, whereas one index case had a heterozygous frameshift change which, if expressed, would generate a truncated protein. This Caucasian child presented with vesicoureteric reflux (VUR), bilateral nephropathy and renal failure. The genetic change was also found in the index case's mother who had normal renal ultrasonography, but it was absent in 150 healthy Caucasian control individuals (96 assessed by direct sequencing and another 54 assessed by restriction digests). UPII was immunolocalized in urothelium of the normal human embryonic renal pelvis in a pattern similar to UPIIIa.
This study offers no definitive support for UPII mutations causing human renal tract malformations. In rare patients, UPII variants might be implicated in pathogenesis when acting in conjunction with other yet-to-be-defined, genetic or environmental modifying factors.
尿血小板溶素（UP）蛋白覆盖尿路上皮的顶端表面。缺乏UPIIIa的小鼠尿路上皮通透性升高且伴有先天性肾道异常，并且在患有肾脏和输尿管畸形的儿童中报道了UPIIIa突变。另一个UP家族成员UPII基因敲除的小鼠常伴有先天性肾积水出生。我们推测UPII突变可能存在于患有肾道畸形的人类中。
对42例患有不同肾道异常的儿童，采用对UPII的5个外显子直接测序的方法寻找突变。
41例患者未检测到UPII异常，而1例索引病例有一个杂合移码改变，如果表达，将产生截短蛋白。这名高加索儿童表现为膀胱输尿管反流（VUR）、双侧肾病和肾衰竭。该基因改变也在索引病例的母亲中发现，其肾脏超声检查正常，但在150名健康的高加索对照个体中未发现（96例通过直接测序评估，另外54例通过限制性酶切评估）。UPII在正常人类胚胎肾盂的尿路上皮中免疫定位，其模式与UPIIIa相似。
本研究没有为UPII突变导致人类肾道畸形提供明确支持。在罕见患者中，当UPII变异与其他尚未明确的遗传或环境修饰因素共同作用时，可能参与发病机制。
