Wu G, Somlo S
Section of Nephrology, Yale School of Medicine, New Haven, Connecticut, 06520, USA.
Mol Genet Metab. 2000 Jan;69(1):1-15. doi: 10.1006/mgme.1999.2943.
Considerable progress toward understanding pathogenesis of autosomal dominant polycystic disease (ADPKD) has been made during the past 15 years. ADPKD is a heterogeneous human disease resulting from mutations in either of two genes, PKD1 and PKD2. The similarity in the clinical presentation and evidence of direct interaction between the COOH termini of polycystin-1 and polycystin-2, the respective gene products, suggest that both proteins act in the same molecular pathway. The fact that most mutations from ADPKD patients result in truncated polycystins as well as evidence of a loss of heterozygosity mechanism in individual PKD cysts indicate that the loss of the function of either PKD1 or PKD2 is the most likely pathogenic mechanism for ADPKD. A novel mouse model, WS25, has been generated with a targeted mutation at Pkd2 locus in which a mutant exon 1 created by inserting a neo(r) cassette exists in tandem with the wild-type exon 1. This causes an unstable allele that undergoes secondary recombination to produce a true null allele at Pkd2 locus. Therefore, the model Pkd2(WS25/-), which carries the WS25 unstable allele and a true null allele, produces somatic second hits during mouse development or adult life and establishes an extremely faithful model of human ADPKD.
在过去15年里，我们对常染色体显性多囊肾病（ADPKD）发病机制的理解取得了显著进展。ADPKD是一种异质性人类疾病，由两个基因PKD1和PKD2中的任何一个发生突变引起。多囊蛋白-1和多囊蛋白-2（各自的基因产物）的COOH末端之间临床表现的相似性以及直接相互作用的证据表明，这两种蛋白质在同一分子途径中发挥作用。大多数ADPKD患者的突变导致截短的多囊蛋白，以及单个PKD囊肿中杂合性缺失机制的证据，这一事实表明，PKD1或PKD2功能的丧失是ADPKD最可能的致病机制。一种新的小鼠模型WS25已通过在Pkd2基因座进行靶向突变而产生，其中通过插入neo(r)盒产生的突变外显子1与野生型外显子1串联存在。这导致一个不稳定的等位基因，该等位基因会经历二次重组，在Pkd2基因座产生一个真正的无效等位基因。因此，携带WS25不稳定等位基因和真正无效等位基因的模型Pkd2(WS25/-)在小鼠发育或成年期会产生体细胞二次打击，并建立了一个极其逼真的人类ADPKD模型。
