OMIA:002133-9615 : Skeletal dysplasia, FGF4-retrogene-related in Canis lupus familiaris
Categories: Skeleton phene (incl. short stature & teeth)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2017
Cross-species summary: A form of disproportionate dwarfism, characterized by short limbs, chondrodystrophy
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: Brown et al. (2017) reported that a "genome-wide association analysis in a cohort of Nova Scotia duck tolling retrievers (NSDTRs) with and without severe SD identified a significant association on CFA12 due to a 12-Mb associated haplotype, of which 1.9 Mb was found to be shared in chondrodystrophoid breeds."
Molecular basis: Brown et al. (2017): an FGF4 retrogene insertion in chromosome CFA12 (12: g.33710178_33710179insMF040221.1; CanFam3) is "responsible for SD [skeletal dysplasia] in NSDTR [Nova Scotia Duck Tolling retrievers] . . . 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." Because the retrogene is not included in NCBI's Gene database, the table below lists the normal FGF4 gene.
Clinical features: Brown et al. (2017): "Relative to the unaffected dog, the mildly SD-affected NSDTR has cranial bowing of the radius. Radiographic changes in the more severely SD-affected NSDTR include moderate cranial bowing of the radius, physeal widening, and incongruity of the elbow joint with the shape of the semilunar notch of the ulna being elongated."
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."
Breed: Nova Scotia Duck Tolling retriever.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|FGF4 retrogene on CFA12||Canis lupus familiaris||-||no genomic information (-..-)||FGF4 retrogene on CFA12||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|
|853||Nova Scotia Duck Tolling retriever||Skeletal dysplasia, FGF4-retrogene-related||FGF4 retrogene on CFA12||FGF4L2||insertion, gross (>20)||Naturally occurring variant||CanFam3.1||12||" 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) . . . ." 200922: g. info moved here (g.33710178_33710179insMF040221) until can be standardised||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.
|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.|
|2019||Tellegen, A.R., Dessing, A.J., Houben, K., Riemers, F.M., Creemers, L.B., Mastbergen, S.C., Meij, B.P., Miranda-Bedate, A., Tryfonidou, M.A. :|
|The dog as a model for osteoarthritis: the FGF4 retrogene insertion may matter. J Orthop Res 37:2550-2560, 2019. Pubmed reference: 31373395 . DOI: 10.1002/jor.24432.|
|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.|
|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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