Autosomal dominant polycystic kidney disease in Persian cats: genotypic and phenotypic characterization and elaboration of criteria for ultrasonographic diagnosis

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic renal disease in humans, affecting 1 in 400-1000 individuals and accounting for 4.4 to 10% of end-stage renal disease cases. This disorder is caused by mutations in one of two genes, PKD1 (polycystic kidney disease 1) or PKD2, with ~85% of the cases occurring due to mutations in PKD1. Similarly, feline ADPKD constitutes the most prevalent inherited illness in domestic cats, affecting 35 to 60% of Persian cats. It must be noted that the lack of epidemiologic data on feline ADPKD in our country makes its control a challenge to veterinary medicine in Brazil. Following the systemic nature of human ADPKD, feline ADPKD is characterized by the development of multiple cysts in renal cortex and medulla and, occasionally, in liver and pancreas. In Persian race, the vast majority of the cases are caused by a C>A substitution in position 138 of exon 29 of the gene orthologous to human PKD1, also called PKD1. This mutation is associated with the creation of a premature stop codon. Different studies have shown correlation between this mutation and ultrasonographic findings consistent with ADPKD. Despite these advances, veterinary medicine still faces three major problems with respect to the establishment of diagnosis for this disorder in cats: 1) The access to the molecular diagnostic test is precarious in veterinary practice; 2) In a small part of Persian and mixed blood cats with presumptive diagnosis of this disease, the C>A mutation in position 138 of exon 29 is not identified, suggesting that in these cases ADPKD occurs due to other mutations; and 3) The temporal course of the renal cystic phenotype is not known/characterized enough in cats confirmed with this disease, which prevents the sure application of the ultrasonographic technique for diagnostic purpose in relatively young animals. In this scenario, our study has the following specific aims: 1) To characterize the qualitative and quantitative phenotype of ADPKD in cats of the Persian race in different age ranges, at the renal, hepatic and pancreatic levels, with ultrasonographic, biochemical, hematological and urinary analyses; 2) To identify and characterize potential genetic variants in the PKD1 gene, to associate them with ADPKD, and to define its prevalence in a Brazilian Persian cat population; and 3) To establish ultrasonographic criteria for the diagnosis of ADPKD in domestic cats, based on the determination of genotype-phenotype correlations for different age ranges in the studied population. We anticipate that this project will be translated into results of high scientific and clinical expression to veterinary medicine. Given the strong clinical similarity between feline and human ADPKD and the limits of data transposition between murine cystic models and human ADPKD, we also anticipate that the findings yielded by the proposed study will acquire considerable human medical relevance. (AU)