OMIA:002542-9615 : Chondrodysplasia, FGF4 retrogene-related in Canis lupus familiaris
Categories: Skeleton phene (incl. short stature & teeth)
Possibly relevant human trait(s) and/or gene(s) (MIM number): 164980 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal
Considered a defect: no
Key variant known: yes
Year key variant first reported: 2009
Species-specific description: "Two FGF4 retrogenes (FGF4L1 on chromosome 18 and FGF4L2 on chromosome 12) have been identified to cause dwarfism across many dog breeds. Some breeds are nearly homozygous for both retrogenes (e.g., Dachshunds) and others are homozygous for just one (e.g., Beagles and Scottish Terriers)" (Bannasch et al., 2022)
Inheritance: Bannasch et al. (2022): "Using individual measurements of height at the shoulder, back length, head width, thorax depth and width, and thoracic limb measurements, we evaluated the combined effects of FGF4 retrogenes [FGF4L1 and FGF4L2] within" two breeds that segregate both retrogenes, namely Alpine Dachsbracke and the Schweizer Niederlaufhund. They found that "both retrogenes had significant effects reducing height at the shoulders and antebrachial length, with FGF4L1 having a much greater effect than FGF4L2. FGF4L1 alone influenced the degree of carpal valgus and FGF4L2 alone increased head width. Neither retrogene had an effect on thorax width or depth."
Mapping: In a mammoth GWAS on 95 chondrodysplastic dogs from 8 breeds and 702 non-chondrodysplastic dogs from 64 breeds, each genotyped with the Affymetrix version 2.0 SNP chip (yielding 41,635 informative SNPs for analysis), Parker et al. (2009) highlighted a 431kb region on chromosome CFA18.
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 a likely causal FGF4 retrogene.
For the mapping of a similar phenotype in other breeds to a likely causal variant on chromsome CFA18, see Brown et al. (2017) in OMIA 000157-9615.
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.
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".
Prevalence: Parker et al. (2009) reported that the CFA18 FGF4 retrogene insertion is fixed (i.e. freq = 1) in the 15 chondrodysplastic breeds listed below.
Control: Bannash et al. (2022) recommend that "Selectively breeding dogs with FGF4L1 and without FGF4L2 would likely lead to a reduction in the FGF4L2-related risk of intervertebral disc herniation while maintaining the reduction in leg length resulting from FGF4L1."
Breeds: Basset Hound, Cairn Terrier, Cardigan Welsh Corgi, Dachshund, Dandie Dinmont Terrier, Lancashire heeler, Norwich Terrier, Pekingese, Pembroke Welsh Corgi, Petit Basset Griffon Vendéen, Shih-Tzu, Skye Terrier, Swedish Vallhund, Tibetan Spaniel, West Highland Terrier.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|FGF4 retrogene CFA18||Canis lupus familiaris||-||no genomic information (-..-)||FGF4 retrogene CFA18||Ensembl|
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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.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|694||Basset Hound Cairn Terrier Cardigan Welsh Corgi Dachshund Dandie Dinmont Terrier Lancashire heeler Norwich Terrier Pekingese Pembroke Welsh Corgi Petit Basset Griffon Vendéen Shih-Tzu Skye Terrier Swedish Vallhund Tibetan Spaniel West Highland Terrier||Chondrodysplasia||FGF4 retrogene CFA18||FGF4L1||insertion, gross (>20)||Naturally occurring variant||18||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 (original) FGF4 gene, which is located at CFA18 48413479-48415205||2009||19608863|
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.
|2022||Bannasch, D., Batcher, K., Leuthard, F., Bannasch, M., Hug, P., Marcellin-Little, D.J., Dickinson, P.J., Drögemüller, M., Drögemüller, C., Leeb, T. :|
|The effects of FGF4 retrogenes on canine morphology. Genes (Basel) 13:325, 2022. Pubmed reference: 35205370 . DOI: 10.3390/genes13020325.|
|Lappalainen, A.K., Pulkkinen, H.S.M., Mölsä, S., Junnila, J., Hyytiäinen, H.K., Laitinen-Vapaavuori, O. :|
|Breed-typical front limb angular deformity is associated with clinical findings in three chondrodysplastic dog breeds. Front Vet Sci 9:1099903, 2022. Pubmed reference: 36733429 . DOI: 10.3389/fvets.2022.1099903.|
|2020||Batcher, K., Dickinson, P., Maciejczyk, K., Brzeski, K., Rasouliha, S.H., Letko, A., Drögemüller, C., Leeb, T., Bannasch, D. :|
|Multiple FGF4 retrocopies recently derived within canids. Genes (Basel) 11:839, 2020. Pubmed reference: 32717834 . DOI: 10.3390/genes11080839.|
|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.|
|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 .|
- Changed by Imke Tammen2 on 22 Mar 2022
- Created by Imke Tammen2 on 22 Mar 2022