Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. 2012

Katharina Hopp, and Christopher J Ward, and Cynthia J Hommerding, and Samih H Nasr, and Han-Fang Tuan, and Vladimir G Gainullin, and Sandro Rossetti, and Vicente E Torres, and Peter C Harris
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.

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.

UI MeSH Term Description Entries
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012720 Severity of Illness Index Levels within a diagnostic group which are established by various measurement criteria applied to the seriousness of a patient's disorder. Illness Index Severities,Illness Index Severity
D016891 Polycystic Kidney, Autosomal Dominant Kidney disorders with autosomal dominant inheritance and characterized by multiple CYSTS in both KIDNEYS with progressive deterioration of renal function. Autosomal Dominant Polycystic Kidney,Kidney, Polycystic, Autosomal Dominant,ADPKD,Adult Polycystic Kidney Disease,Adult Polycystic Kidney Disease Type 1,Adult Polycystic Kidney Disease Type 2,Polycystic Kidney Disease 2,Polycystic Kidney Disease, Adult,Polycystic Kidney Disease, Adult Type 2,Polycystic Kidney Disease, Adult, Type II,Polycystic Kidney Disease, Autosomal Dominant,Polycystic Kidney Disease, Type 2,Polycystic Kidney, Type 1 Autosomal Dominant Disease,Polycystic Kidney, Type 2 Autosomal Dominant Disease
D017510 Protein Folding Processes involved in the formation of TERTIARY PROTEIN STRUCTURE. Protein Folding, Globular,Folding, Globular Protein,Folding, Protein,Foldings, Globular Protein,Foldings, Protein,Globular Protein Folding,Globular Protein Foldings,Protein Foldings,Protein Foldings, Globular
D050396 TRPP Cation Channels A subgroup of TRP cation channels that are widely expressed in various cell types. Defects are associated with POLYCYSTIC KIDNEY DISEASES. Polycystin,Polycystins,Cation Channels, TRPP,Channels, TRPP Cation
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055879 Gene Knock-In Techniques Techniques used to add in exogenous gene sequence such as mutated genes; REPORTER GENES, to study mechanisms of gene expression; or regulatory control sequences, to study effects of temporal changes to GENE EXPRESSION. Gene Knock In,Gene Knock In Techniques,Gene Knock-In,Gene Knock Ins,Gene Knock-In Technique,Gene Knock-Ins,In, Gene Knock,Ins, Gene Knock,Knock In, Gene,Knock Ins, Gene,Knock-In Technique, Gene,Knock-In Techniques, Gene,Knock-In, Gene,Knock-Ins, Gene,Technique, Gene Knock-In,Techniques, Gene Knock-In
D056426 Genetic Loci Specific regions that are mapped within a GENOME. Genetic loci are usually identified with a shorthand notation that indicates the chromosome number and the position of a specific band along the P or Q arm of the chromosome where they are found. For example the locus 6p21 is found within band 21 of the P-arm of CHROMOSOME 6. Many well known genetic loci are also known by common names that are associated with a genetic function or HEREDITARY DISEASE. Genetic Locus,Loci, Genetic,Locus, Genetic
D019943 Amino Acid Substitution The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. Amino Acid Substitutions,Substitution, Amino Acid,Substitutions, Amino Acid

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