PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism.

Gabriela Rudd Garces,Myriam Muracchini,Alessia Diana,Fabio Gentilini,Vidhya Jagannathan,Maria Elena Turba,Tosso Leeb

doi:10.3390/genes12101489

Gabriela Rudd Garces, Myriam Muracchini + Show 5 more

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https://doi.org/10.3390/genes12101489

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Abstract

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.

Highlights

Introduction iationsSkeletal dysplasias are a large, heterogeneous group of genetic disorders characterized by the abnormal growth, development and remodeling of bones and cartilage [1].The Nosology Committee of the International Skeletal Dysplasia Society recognizes 461 different diseases, which are classified into 42 groups based on their clinical, radiographic, and molecular phenotypes
A breeder of Dogo Argentino dogs identified two half-sibling puppies, one male and one female, with skeletal deformities that became evident at 2 months of age
We identified a new form of disproportionate dwarfism in Dogo Ar4

Summary

Introduction

Skeletal dysplasias are a large, heterogeneous group of genetic disorders characterized by the abnormal growth, development and remodeling of bones and cartilage [1]. The Nosology Committee of the International Skeletal Dysplasia Society recognizes 461 different diseases, which are classified into 42 groups based on their clinical, radiographic, and molecular phenotypes. Next-generation sequencing technologies have allowed for the identification of the causal variants affecting 437 different genes in 425 of these disorders [2]. Dwarfism is the medical term used to denote short stature, and according to the Online. Mendelian Inheritance in Man (https://www.omim.org/ (accessed on 16 September 2021), there are more than 200 different types of underlying skeletal dysplasias in patients with primary or secondary dwarfism phenotypes. Based on the specific phenotype, dwarfism can be classified as proportionate or disproportionate.

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