PKD1 Nonsense Variant in a Lagotto Romagnolo Family with Polycystic Kidney Disease

• Published in: Genes
• Main Authors: Michaela Drögemüller, Nadine Klein, Rikke Lill Steffensen, Miriam Keiner, Vidhya Jagannathan, Tosso Leeb
• Format: Text
• Language: English
• Published: Multidisciplinary Digital Publishing Institute 2023
• Subjects: Canis lupus familiaris; dog; whole genome sequencing; de novo; precision medicine; HRFCD; ADPKD; animal model; Canis lupus
• Online Access: https://doi.org/10.3390/genes14061210

A female Lagotto Romagnolo dog with polycystic kidney disease (PKD) and her progeny, including PKD-affected offspring, were studied. All affected dogs appeared clinically inconspicuous, while sonography revealed the presence of renal cysts. The PKD-affected index female was used for breeding and produced two litters with six affected offspring of both sexes and seven unaffected offspring. The pedigrees suggested an autosomal dominant mode of inheritance of the trait. A trio whole genome sequencing analysis of the index female and her unaffected parents identified a de novo heterozygous nonsense variant in the coding region of the PKD1 gene. This variant, NM_001006650.1:c.7195G>T, is predicted to truncate 44% of the open reading frame of the wild-type PKD1 protein, NP_001006651.1:p.(Glu2399*). The finding of a de novo variant in an excellent functional candidate gene strongly suggests that the PKD1 nonsense variant caused the observed phenotype in the affected dogs. Perfect co-segregation of the mutant allele with the PKD phenotype in two litters supports the hypothesized causality. To the best of our knowledge, this is the second description of a PKD1-related canine form of autosomal dominant PKD that may serve as an animal model for similar hepatorenal fibrocystic disorders in humans.