Abstract
Two FGF4 retrogenes on chromosomes 12 (12-FGF4RG) and 18 (18-FGF4RG) contribute to short-limbed phenotypes in dogs. 12-FGF4RG has also been associated with intervertebral disc disease (IVDD). Both of these retrogenes were found to be widespread among dog breeds with allele frequencies ranging from 0.02 to 1; however, their additive contribution to disease is unknown. Surgical cases of IVDD (n = 569) were evaluated for age of onset, disc calcification, and genotypes for the FGF4 retrogenes. Multivariable linear regression analysis identified the presence of one or two copies of 12-FGF4RG associated with significantly younger age at first surgery in a dominant manner. 18-FGF4RG had only a minor effect in dogs with one copy. Multivariable logistic regression showed that 12-FGF4RG had an additive effect on radiographic disc calcification, while 18-FGF4RG had no effect. Multivariable logistic regression using mixed breed cases and controls identified only 12-FGF4RG as highly associated with disc herniation in a dominant manner (Odds Ratio, OR, 18.42, 95% Confidence Interval (CI) 7.44 to 50.26; p < 0.001). The relative risk for disc surgery associated with 12-FGF4RG varied from 5.5 to 15.1 within segregating breeds and mixed breeds. The FGF4 retrogene on CFA12 acts in a dominant manner to decrease the age of onset and increase the overall risk of disc disease in dogs. Other modifiers of risk may be present within certain breeds, including the FGF4 retrogene on CFA18.
Highlights
The domestic dog exhibits a profound degree of phenotypic diversity in size
12-FGF4RG was the only factor contributing to intervertebral disc disease (IVDD) surgery in mixed breed dogs
We report that 12-FGF4RG is both associated with intervertebral disc calcification and with age at time of surgery for IVDD across all affected breeds
Summary
Two particular conditions affecting size, referred to as chondrodystrophy and chondrodysplasia, are characterized by shortened limbs and are common across many dog breeds [1,2]. The causes for both chondrodystrophy and chondrodysplasia were identified as two separate fibroblast growth factor 4 (FGF4) retrogenes on chromosome 12 (12-FGF4RG) and chromosome 18 (18-FGF4RG), respectively [1,2]. Higher levels of FGF4 transcripts were seen in dogs with either of the 12-FGF4RG or 18-FGF4RG insertions, leading to the conclusions that the FGF4 retrogenes are expressed and that the short-limb phenotype is associated with overexpression during development [1,2]. Achondroplasia, the most common form of dwarfism, is caused by the gain of function variants in the fibroblast growth factor receptor 3 that results in increased signaling [7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
