OMIA 000187-9615 : Chondrodysplasia in Canis lupus familiaris
By conducting a proof-of-principal across-breed GWAS on 18 affected (from 6 breeds, and including 3 crossbred dogs) and 27 control dogs from 11 breeds (and including 4 crossbred dogs), each genotyped with the Affymetrix Version 2 Custom Canine SNP (comprising 49,663 SNPs), Bannasch et al. (2010) highlighted the same region on chromosome CFA18 that had been shown by Parker et al. (2009) to harbour the likely causal FGF4 retrogene.
Brown et al. (2017) reported that a "genome-wide association analysis of Hansen’s type I IVDD [see OMIA 000157-9615] across breeds localized . . . [a] 1.9-Mb region on CFA12 [exactly the same region to which these same authors had mapped skeletal dysplasia in Nova Scotia Duck Tolling retrievers, NSDTR; see OMIA 002133-9615], suggesting that the locus responsible for SD in the NSDTR is also responsible for type I IVDD and the chondrodystrophoid phenotype across dog breeds".Molecular basis: Sequencing within the candidate region (see Mapping section) by Parker et al. (2009) revealed the likely causal mutation to be a 5kb insertion containing a FGF4 retrogene, i.e. a processed pseudogene of FGF4: "Neither the introns nor the upstream promoter sequences of the gene were present in the insert, however all exons were present, with no alterations in the coding sequence, as well as the 3’ UTR and poly-A tail characteristic of retrotransposition of processed mRNA". Furthermore, "The retrogene is inserted in the middle of a LINE with both LINEs and SINEs upstream". The authors suggested "that atypical expression of the [retrogen] FGF4 transcript in the chondrocytes may be causing inappropriate activation of one or more of the fibroblast growth factor receptors such as FGFR3", mutations in which account for the majority of dwarfism cases in humans. The insertion containing the FGF4 retrogene starts at 23,431,136 on CFA18, which is 25Mb away from the complete FGF4 gene, which is located at 48413479-48415205. Because the retrogene is not included in NCBI's Gene database, the table below lists the normal FGF4 gene.
As noted by Brown et al. (2017), despite its obvious importance, the above insertion variant "failed to explain breeds such as the American cocker spaniel, beagle, and French bulldog, that in addition to dachshunds, were the breeds originally classified as chondrodystrophoid based on histopathologic and morphologic analysis" by Hansen (1951, 1952) and Braund et al. (1975).
Within their candidate region on CFA12 (see Mapping section above), Brown et al. (2017) identified a likely causal variant, namely an FGF4 retrogene insertion in chromosome CFA12 (12: g.33710178_33710179insMF040221.1; CanFam3), . . . the insertion on CFA12 is 3,209 bp long (GenBank accession no. MF040221) and includes parental FGF4 cDNA (i.e., FGF4 exons spliced without introns) . . . . The insert also contains a majority of the predicted 5′-untranslated region (UTR), which includes the transcription start site (TSS) as only PCR primers FGF4_TSS.F1 and FGF4.R1 yielded a product in RT-PCR using cDNA from neonatal beagle IVD . . . . The insertion location is intergenic between the 3′-UTR of OGFRL1 ∼9.5 kb on the proximal side and ∼350 kb to the RIMS1 gene on the distal side."Clinical features: Even though chondrodysplasia is normally regarded as a defect, this canine mutation is not classified as a defect because, as noted by Parker et al. (2009), it is a "a short-legged phenotype that defines at least 19 dog breeds including dachshund, corgi, and basset hound". Breeds: Basset Hound, Dachshund, Pembroke Welsh Corgi. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|FGF4||fibroblast growth factor 4||Canis lupus familiaris||18||NC_006600.3 (48413480..48417494)||FGF4||Homologene, Ensembl, NCBI gene|
By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.
WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Year Published||PubMed ID(s)||Acknowledgements|
|Chondrodysplasia||FGF4||insertion, gross (>20)||a 5kb insertion containing a FGF4 retrogene, i.e. a processed pseudogene of FGF4: The insertion containing the FGF4 retrogene starts at 23,431,136 on CFA18, which is 25Mb away from the complete FGF4 gene, which is located at 48413479-48415205||2009||19608863|
|Chondrodysplasia||FGF4||insertion, gross (>20)||CanFam 3||12||g.33710178_33710179insMF040221||" the insertion on CFA12 is 3,209 bp long (GenBank accession no. MF040221) and includes parental FGF4 cDNA (i.e., FGF4 exons spliced without introns) . . . ."||2017||29073074|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2017||Brown, E.A., Dickinson, P.J., Mansour, T., Sturges, B.K., Aguilar, M., Young, A.E., Korff, C., Lind, J., Ettinger, C.L., Varon, S., Pollard, R., Brown, C.T., Raudsepp, T., Bannasch, D.L. :|
|FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs. Proc Natl Acad Sci U S A 114:11476-11481, 2017. Pubmed reference: 29073074. DOI: 10.1073/pnas.1709082114.|
|2010||Bannasch, D., Young, A., Myers, J., Truvé, K., Dickinson, P., Gregg, J., Davis, R., Bongcam-Rudloff, E., Webster, M.T., Lindblad-Toh, K., Pedersen, N. :|
|Localization of canine brachycephaly using an across breed mapping approach. PLoS One 5:e9632, 2010. Pubmed reference: 20224736. DOI: 10.1371/journal.pone.0009632.|
|2009||Kaessmann, H. :|
|Genetics. More than just a copy. Science 325:958-9, 2009. Pubmed reference: 19696341. DOI: 10.1126/science.1178487.|
|Parker, HG., Vonholdt, BM., Quignon, P., Margulies, EH., Shao, S., Mosher, DS., Spady, TC., Elkahloun, A., Cargill, M., Jones, PG., Maslen, CL., Acland, GM., Sutter, NB., Kuroki, K., Bustamante, CD., Wayne, RK., Ostrander, EA. :|
|An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 325:995-8, 2009. Pubmed reference: 19608863. DOI: 10.1126/science.1173275.|
|2008||Young, AE., Bannasch, DL. :|
|SNPS in the promoter regions of the canine RMRP and SHOX genes are not associated with canine chondrodysplasia. Anim Biotechnol 19:1-5, 2008. Pubmed reference: 18228171. DOI: 10.1080/10495390701638328.|
|1994||Bingel, S.A., Sande, R.D. :|
|Chondrodysplasia in five Great Pyrenees Journal of the American Veterinary Medical Association 205:845-848, 1994. Pubmed reference: 7829378.|
|1975||Braund, K.G., Ghosh, P., Taylor, T.K.F., Larsen, L.H. :|
|Morphological studies of the canine intervertebral disc: the assignment of the Beagle to the achondroplastic classification Research in Veterinary Science 19:167-172, 1975. Pubmed reference: 1166121.|
|1952||Hansen, H.J. :|
|A pathologic-anatomical study on disc degeneration in dog, with special reference to the so-called enchondrosis intervertebralis. Acta Orthop Scand Suppl 11:1-117, 1952. Pubmed reference: 14923291.|
|1951||Hansen, H.J. :|
|A pathologic-anatomical interpretation of disc degeneration in dogs. Acta Orthop Scand 20:280-93, 1951. Pubmed reference: 14894198.|
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