Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity.
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.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Katharina
K
Hopp
Christopher J
CJ
Ward
Cynthia J
CJ
Hommerding
Samih H
SH
Nasr
Han-Fang
HF
Tuan
Vladimir G
VG
Gainullin
Sandro
S
Rossetti
Vicente E
VE
Torres
Peter C
PC
Harris
D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D056426:Genetic Loci; D051379:Mice; D020125:Mutation, Missense; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D012720:Severity of Illness Index; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
D050396:TRPP Cation Channels