Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway
Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway
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DOI：
10.1093/hmg/ddm141
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发表时间：
2007-08-15
影响因子：
3.5
通讯作者：
Germino, Gregory G.
中科院分区：
文献类型：
--
作者：
Garcia-Gonzalez, Miguel A.;Menezes, Luis F.;Germino, Gregory G.
多囊肾病(PKD)描述了一组在病因和临床表现上有显著不同的疾病。然而，它们都有一个共同的特征，即不正常的小管形态，导致假设它们各自的基因产物可能在共同的途径中协同作用，以维持小管的完整性。为了研究人类PKD的一种主要形式的病理生物学，我们建立了一个带有Pkhd1的小鼠系，Pkhd1是人类常染色体隐性遗传性PKD基因突变的同源基因。Cre介导的外显子3-4的切除可能导致一个亚型等位基因。Pkhd(1del3-4/del3-4)发展了一系列的表型，概括了人类疾病的关键特征。就像人类一样，胆道的异常是一个不变的发现。大多数6个月或以上的小鼠也出现了肾囊肿。出现围产期呼吸衰竭或表现出非肾脏疾病所致的生长迟缓的动物亚组。然后我们测试了Pkhd1和PKd1之间的遗传相互作用，PKd1是该基因的小鼠同源基因，最常与人类常染色体显性PKD联系在一起。PKD1(+/-)、Pkhd1(del3-4/del3-4)小鼠的病情明显重于PKD1(+/+)、Pkhd1(del3-4/del3-4)小鼠。这些研究首次表明，在一个共同的PKD途径中，导致人类肾囊性疾病的主要基因座之间存在遗传相互作用。
Polycystic kidney disease (PKD) describes a heterogeneous collection of disorders that differ significantly with respect to their etiology and clinical presentation. They share, however, abnormal tubular morphology as a common feature, leading to the hypothesis that their respective gene products may function cooperatively in a common pathway to maintain tubular integrity. To study the pathobiology of one major form of human PKD, we generated a mouse line with a floxed allelle of Pkhd1, the orthologue of the gene mutated in human autosomal recessive PKD. Cre-mediated excision of exons 3-4 results in a probable hypomorphic allele. Pkhd(1del3-4/del3-4) developed a range of phenotypes that recapitulate key features of the human disease. Like in humans, abnormalities of the biliary tract were an invariant finding. Most mice 6 months or older also developed renal cysts. Subsets of animals presented with either perinatal respiratory failure or exhibited growth retardation that was not due to the renal disease. We then tested for genetic interaction between Pkhd1 and Pkd1, the mouse orthologue of the gene most commonly linked to human autosomal dominant PKD. Pkd1(+/-); Pkhd1(del3-4/del3-4) mice had markedly more severe disease than Pkd1(+/+); Pkhd1(del3-4/del3-4) littermates. These studies are the first to show genetic interaction between the major loci responsible for human renal cystic disease in a common PKD pathway.