Prkg2 splice site variant in dogo argentino dogs with disproportionate dwarfism

• Published in: Genes
• Main Authors: Rudd Garces G., Turba M. E., Muracchini M., Diana A., Jagannathan V., Gentilini F., Leeb T.
• Other Authors: Turba M.E.
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2021
• Subjects: Bone; Canis lupus familiari; Development; Growth; Homozygosity mapping; Linkage analysi; Whole genome sequencing; Animal; Cattle; Cyclic GMP-Dependent Protein Kinase Type II; Dog Disease; Dog; Dwarfism; Genetic Linkage; Genotype; Human; Mice; Mutation; Pedigree; Phenotype; Protein Isoform; Rat; Genetic Predisposition to Disease; Canis lupus
• Online Access: https://hdl.handle.net/11585/861905; https://doi.org/10.3390/genes12101489

Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a decreased level of endochondral ossification in its growth plates, and a premature closure of the distal ulnar physes. The pedigree of the dogs presented evidence of monogenic autosomal recessive inheritance; combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 34 genome segments, totaling 125 Mb. The genome of an affected dog was sequenced and compared to 795 control genomes. The prioritization of private variants revealed a clear top candidate variant for the observed dwarfism. This variant, PRKG2:XM_022413533.1:c.1634+1G>T, affects the splice donor site and is therefore predicted to disrupt the function of the PKRG2 gene encoding protein, kinase cGMP-dependent type 2, a known regulator of chondrocyte differentiation. The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs. PRKG2 loss-of-function variants were previously reported to cause disproportionate dwarfism in humans, cattle, mice, and rats. Together with the comparative data from other species, our data strongly suggest PRKG2:c.1634+1G>T to be a candidate causative variant for the observed dwarfism phenotype in Dogo Argentino dogs.