Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity
Katharina Hopp, … , Vicente E. Torres, Peter C. Harris
Katharina Hopp, … , Vicente E. Torres, Peter C. Harris
Published October 15, 2012
Citation Information: J Clin Invest. 2012;122(11):4257-4273. https://doi.org/10.1172/JCI64313.
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Research Article

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Abstract

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, Pkd1RC/null mice have rapidly progressive disease, and Pkd1RC/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.

Authors

Katharina Hopp, Christopher J. Ward, Cynthia J. Hommerding, Samih H. Nasr, Han-Fang Tuan, Vladimir G. Gainullin, Sandro Rossetti, Vicente E. Torres, Peter C. Harris

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Figure 4

Pkd1RC/null mice develop in utero/early-onset ADPKD.

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Pkd1RC/null mice develop in utero/early-onset ADPKD. (A) Gross images...
(A) Gross images of WT and Pkd1RC/del2 kidneys from P1 to P180, illustrating early-onset/rapidly progressive disease. After P25, the kidney size decreased, likely due to increased fibrosis (Figure 5 and Table 1). The ruler depicts centimeters. (B) Kaplan-Meier curve of WT and Pkd1RC/del2 mice. Eighty percent of Pkd1RC/del2 mice died before P50 (median survival, P28 [arrow]; n = 55/group). (C–E) Graphical representations of %KW/BW, BUN, and cAMP from P1 to P25 of Pkd1RC/del2 animals (Supplemental Table 2). (C) %KW/BW was significantly increased as early as P1 (3%) and rapidly climbed to 25% by P25. (D) BUN levels rose beyond the physiological average as early as P18. (E) cAMP levels were significantly above normal by P1. Values in C–E were obtained from n ≥ 5 at each time point for both WT and Pkd1RC/del2 mice. P180 data can be found in Supplemental Table 2. Statistical values were obtained by the Student’s t test (*P < 0.05, **P < 0.01, ***P < 0.001); error bars indicate ± SD.