Lu W, Peissel B, Babakhanlou H, Pavlova A, Geng L, Fan X, Larson C, Brent G, Zhou J
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Genet. 1997 Oct;17(2):179-81. doi: 10.1038/ng1097-179.
PKD1 is the most common site for mutations in human autosomal dominant polycystic kidney disease (ADPKD). ADPKD is characterized by progressive replacement of kidney tissue by epithelial cysts and eventual renal failure. Hepatic and pancreatic cysts are also common. The PKD1 protein, polycystin, is a cell-surface protein of unknown function that is widely expressed in epithelia and in vascular smooth muscle and myocardium. None of the genetic forms of murine polycystic disease map to the murine Pkd1 locus. We introduced into mice by homologous recombination a Pkd1 truncation mutation, Pkd1-, that mimics a mutation found in ADPKD. Pkd1- heterozygotes have no discernible phenotype, whereas homozygotes die during the perinatal period with massively enlarged cystic kidneys, pancreatic ductal cysts and pulmonary hypoplasia. Renal cyst formation begins at embryonic day 15.5 (E15.5) in proximal tubules and progresses rapidly to replace the entire renal parenchyma. The timing of cyst formation indicates that full-length polycystin is required for normal morphogenesis during elongation and maturation of tubular structures in the kidney and pancreas.
PKD1是人类常染色体显性遗传性多囊肾病（ADPKD）中最常见的突变位点。ADPKD的特征是肾组织逐渐被上皮囊肿取代并最终导致肾衰竭。肝囊肿和胰腺囊肿也很常见。PKD1蛋白，即多囊蛋白，是一种功能未知的细胞表面蛋白，广泛表达于上皮细胞、血管平滑肌和心肌中。小鼠多囊病的任何遗传形式都不定位到小鼠Pkd1基因座。我们通过同源重组将一种模拟在ADPKD中发现的突变的Pkd1截短突变（Pkd1-）导入小鼠体内。Pkd1-杂合子没有明显的表型，而纯合子在围产期死亡，伴有大量增大的多囊肾、胰腺导管囊肿和肺发育不全。肾囊肿形成于胚胎第15.5天（E15.5）的近端小管，并迅速发展以取代整个肾实质。囊肿形成的时间表明全长多囊蛋白是肾脏和胰腺中管状结构伸长和成熟过程中正常形态发生所必需的。
