Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs

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.

Pathologic Features of the Intervertebral Disc in Young Nova Scotia Duck Tolling Retrievers Confirms Chondrodystrophy Degenerative Phenotype Associated With Genotype

“…The chondrodystrophic degenerative phenotype is evident in the IVD as early as 10 weeks of age in dogs homozygous for the CFA12 FGF4 retrogene but is absent in breedmatched dogs lacking the mutation. These degenerative changes are similar to the detailed descriptions of degenerative "chondroid metamorphosis" in several chondrodystrophic dog breeds originally documented by Hansen 13 and those described in the Beagle and Dachshund breeds by Braund et al 5 Based on known genotyping data, 1,7 the dog breeds studied by Hansen 13 and Braund et al 5 (particularly Dachshunds and Beagles) would have had a high likelihood of carrying the CFA12 FGF4 retrogene due to the limited segregation of the allele within those breeds (allele frequencies of 0.99 and 1.0, respectively, based on UC Davis data). While Dachshunds also have a very high allele frequency for CFA18 FGF4 retrogene (0.99), Beagles do not appear to carry the CFA18 FGF4 retrogene.…”

“…20,25,31 Classification based on gross morphological traits is problematic since a short-limbed phenotype may be associated with the CFA18 FGF4 retrogene or the CFA12 FGF4 retrogene, and only the latter appears to also result in the chondrodystrophic phenotype with concurrent degeneration of the IVD. 1,7 The presence of the CFA12 and CFA18 retrogenes is variable among many small dog breeds, and many breeds segregate both CFA12 and CFA18 FGF4 retrogenes. 1,7 Also, a single copy of the CFA12 FGF4 retrogene appears to be sufficient to cause IVD degeneration, but effects on limb length appear to be related to gene dose, making "longer legged" heterozygous animals more challenging to define as chondrodystrophic.…”

“…1,7 The presence of the CFA12 and CFA18 retrogenes is variable among many small dog breeds, and many breeds segregate both CFA12 and CFA18 FGF4 retrogenes. 1,7 Also, a single copy of the CFA12 FGF4 retrogene appears to be sufficient to cause IVD degeneration, but effects on limb length appear to be related to gene dose, making "longer legged" heterozygous animals more challenging to define as chondrodystrophic. 7 Defining CFA12 FGF4 retrogene status in future studies is likely to clarify some of these issues, but the heterogeneity of IVDD phenotypes makes it likely that additional genetic factors are contributing to disease presentation.…”

“…In addition, premature chondroid degeneration and mineralization of IVDs can be seen, albeit less frequently, in nonchondrodystrophic breeds 8,9 and specifically in those that do not carry the CFA12 FGF4 retrogene. 1 IVDD in these animals may result from alternative mechanisms affecting the same FGF-related biology of the IVD (in the absence of limb length alterations) or may represent novel pathway alterations resulting in a common phenotype.…”

Dog Breeds and Body Conformations with Predisposition to Osteosarcoma in the UK: A Case-Control Study

“…For example, Rhodesian Ridgebacks are owned by a lower proportion of the general population than Rottweilers (1.7% Rhodesian Ridgeback versus 7.9% Rottweiler ownership within VetCompass), which could have led to case-only studies underestimating the prevalence of osteosarcoma within Rhodesian Ridgebacks, because they present less often to the clinic owing to reduced ownership [5]. Having used a case and a control population, the current study design enabled us to minimize the likelihood of selective sampling, therefore we demonstrated that, as a proportion of Rhodesian Ridgebacks owned, their osteosarcoma risk is actually high [33,35]. Our results also differ from previous studies which determined that Staffordshire Bull Terriers (SBT) commonly present to veterinary clinics with osteosarcoma, and therefore cited SBT as an at-risk breed [5].…”