PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism

• Published in: Genes
• Main Authors: Gabriela Rudd Garces, Maria Elena Turba, Myriam Muracchini, Alessia Diana, Vidhya Jagannathan, Fabio Gentilini, Tosso Leeb
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI AG 2021
• Subjects: Canis lupus familiaris; linkage analysis; homozygosity mapping; whole genome sequencing; bone; growth; Genetics; QH426-470; Argentino; Canis lupus
• Online Access: https://doi.org/10.3390/genes12101489; https://doaj.org/article/9ed0930d757f44c296ef175c0d9b6201

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.