Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity
Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity
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DOI：
10.1172/jci64313
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发表时间：
2012-11-01
影响因子：
15.9
通讯作者：
Harris, Peter C.
中科院分区：
文献类型：
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作者：
Hopp, Katharina;Ward, Christopher J.;Harris, Peter C.
常染色体显性多囊肾病 (ADPKD) 是由 PKD1 或 PKD2 突变引起的，会引发进行性囊肿发生，通常会导致中年终末期肾病。然而，表型谱范围从子宫内发病到老年肾功能充足。最近的患者数据表明，该疾病具有剂量依赖性，其中不完全渗透的等位基因影响疾病的严重程度。在这里，我们开发了一种与可能的疾病变异 PKD1 p.R3277C (RC) 相匹配的敲入小鼠模型，并证明其功能亚型性质改变了 ADPKD 表型。虽然 Pkd1(+/null) 小鼠是正常的，但 Pkd1(RC/null) 小鼠的疾病进展迅速，而 Pkd1(RC/RC) 动物则逐渐发生囊肿发生。这些模型分别有效地模拟了子宫内发病和典型 ADPKD 的病理生理学特征，将功能性 Pkd1 产物的水平与疾病严重程度相关联，突出了囊肿发生的剂量依赖性。此外，分子分析发现 p.R3277C 是一种温度敏感的折叠/运输突变体，据我们所知，首次在 PKD1 中清楚地检测到集合管初级纤毛（PKD 发病机制的核心细胞器）的长度缺陷。总而言之，这项研究强调了疾病位点的反式变异在显性疾病的表型修饰中所发挥的作用，并提供了一个真正的直系同源 PKD1 模型，最适合治疗测试。
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1(+/null) mice are normal, Pkd1(RC/null) mice have rapidly progressive disease, and Pkd1(RC/RC) animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkd1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.