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 2

Homozygosity of the Pkd1 p.R3277C allele results in progressive PKD with physiological characteristics comparable to those of human ADPKD.

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Homozygosity of the Pkd1 p.R3277C allele results in progressive PKD with...
(A) Representative US M-mode images of Pkd1RC/RC mice. Kidneys with the mildest (left) and most severe disease (right) are shown at 3 months. Kidney cysts are visible as echolucent spots (arrows). Scale bars: 10 mm (left); 12 mm (right). (B) Quantification of US at 3, 6, 9, and 12 months of each individual animal and the mean of all animals. Significant differences between WT and homozygotes were seen at all time points. KV increased in most animals progressively, but variability among mice was observed. (C–E) Graphic representations of %KW/BW, cAMP, and BUN measured at 3, 6, 9, and 12 months (Supplemental Table 1). (C) %KW/BW increased progressively with cyst burden until 9 months, after which a significant decrease was observed, likely correlated with increased fibrosis (Table 1). (D) Similar to that in patients with ADPKD, cAMP levels rose with disease burden (16). (E) Increased kidney damage due to cystogenesis/fibrosis resulted in a significantly elevated BUN after 9 months. The data in C–E were obtained from the same group of animals at each time point (WT, n = 4; Pkd1RC/RC, n = 6). Statistical values were obtained by the Student’s t test (*P < 0.05, **P < 0.01, ***P < 0.001); error bars indicate ± SD.