OMIA 001926-9913 : Achondrogenesis, type II in Bos taurus
Agerholm et al. (2016) reported a different likely COL2A1 causal mutation in Danish Holstein cattle: g.32473300 G>A; c.2463 + 1G>A: "This private sequence variant was predicted to affect splicing as it altered the conserved splice donor sequence GT at the 5’-end of COL2A1 intron 36, which was changed to AT. All five available cases carried the mutant allele in heterozygous state and all five dams were homozygous wild type. The sire VH Cadiz Captivo was shown to be a gonadal and somatic mosaic as assessed by the presence of the mutant allele at levels of about 5 % in peripheral blood and 15 % in semen".
Bourneuf et al. (2017) reported three de novo likely causal missense variants for this disorder: g.32469820G>A (c.1791G>A; p.G600D) in the offspring of a Charolais (sire) x Salers cross; g.32476082G>A (c.2986G>A; p.G996S) in a Holstein pedigree; and g.32471813G>A (c.2158G>A; p.G720S) in another Holstein pedigree.
Reinartz et al. (2017) reported the above g.32476082G>A (c.2986G>A; p.G996S) variant as being causal in the offspring of another Holstein bull named Energy P.
Häfliger et al. (2019) reported a de novo likely causal variant (g.32476808G>A; c.3166G>A; p.Gly1056Ser) in a Holstein bulldog calf.
Jacinto et al. (2020) reported a de novo likely causal variant (a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons of COL2A1) in a Holstein bulldog calf.Clinical features: Agerholm et al. (2001) provided a detailed clinical description of this lethal phenotype, which they classified as ‘‘Dexter bulldog type", i.e. having similar clinical features to Dwarfism, aggrecan type (OMIA 001271-9913), namely "disproportionate growth retardation characterized by fascial dysplasia and shortening of the vertebral column and the abaxial skeleton. Endochondral osteogenesis was disturbed with disorganization of epiphyseal plate chondrocytes, a lesion consistent with generalized chondrodysplasia".
The combination of these clinical signs with a causal mutation in COL2A1 (as described above) led Daetwyler et al. (2014) to conclude that this disorder is homologous to Achondrogenesis, type II in humans (see OMIM link above).Genetic testing: Importantly, Häfliger et al. (2019) concluded "that the identified COL2A1 p.Gly1056Ser missense variant occurred de novo. It is highly likely that the mutation occurred during early embryonic development of the affected calf. This is exactly the case for one (p.Gly720Ser) of the four BD calf syndromes causing missense variants that were previously reported [Bourneuf et al. (2017)]. For Holstein cattle it is important to recognize that, even within a single breed, phenotypically indistinguishable cases of BD calf syndrome show notable allelic heterogeneity. " Breeds: Charolais, Holstein. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|COL2A1||collagen type II alpha 1||Bos taurus||5||NC_037332.1 (32283180..32313172)||COL2A1||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|
|Holstein||Bulldog calf||COL2A1||delins, gross (>20)||ARS-UCD1.2||5||g.32303127_32306640delinsTCTGGGGAGC||2020||32894162|
|Charolais Salers||Bulldog calf||COL2A1||missense||UMD3.1||5||g.32469820G>A||c.1791G>A||p.G600D||2017||28904385||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|Holstein||Bulldog calf||COL2A1||missense||UMD3.1||5||g.32471813G>A||c.2158G>A||p.G720S||2017||28904385||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|Danish Holstein||bulldog calf||COL2A1||splicing||UMD3.1||5||g.32473300G>A||c.2463+1G>A||2016||27296271||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|Holstein||Bulldog calf||COL2A1||missense||UMD3.1||5||g.32476082G>A||c.2986G>A||p.G996S||rs876243579||2017||28904385||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
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.
|2020||Jacinto, J.G.P., Häfliger, I.M., Letko, A., Drögemüller, C., Agerholm, J.S. :|
|A large deletion in the COL2A1 gene expands the spectrum of pathogenic variants causing bulldog calf syndrome in cattle. Acta Vet Scand 62:49, 2020. Pubmed reference: 32894162. DOI: 10.1186/s13028-020-00548-w.|
|2019||Häfliger, I.M., Behn, H., Freick, M., Jagannathan, V., Drögemüller, C. :|
|A COL2A1 de novo variant in a Holstein bulldog calf. Anim Genet 50:113-114, 2019. Pubmed reference: 30378686. DOI: 10.1111/age.12735.|
|2017||Bourneuf, E., Otz, P., Pausch, H., Jagannathan, V., Michot, P., Grohs, C., Piton, G., Ammermüller, S., Deloche, M.C., Fritz, S., Leclerc, H., Péchoux, C., Boukadiri, A., Hozé, C., Saintilan, R., Créchet, F., Mosca, M., Segelke, D., Guillaume, F., Bouet, S., Baur, A., Vasilescu, A., Genestout, L., Thomas, A., Allais-Bonnet, A., Rocha, D., Colle, M.A., Klopp, C., Esquerré, D., Wurmser, C., Flisikowski, K., Schwarzenbacher, H., Burgstaller, J., Brügmann, M., Dietschi, E., Rudolph, N., Freick, M., Barbey, S., Fayolle, G., Danchin-Burge, C., Schibler, L., Bed'Hom, B., Hayes, B.J., Daetwyler, H.D., Fries, R., Boichard, D., Pin, D., Drögemüller, C., Capitan, A. :|
|Rapid Discovery of De Novo Deleterious Mutations in Cattle Enhances the Value of Livestock as Model Species. Sci Rep 7:11466, 2017. Pubmed reference: 28904385. DOI: 10.1038/s41598-017-11523-3.|
|Reinartz, S., Mohwinkel, H., Sürie, C., Hellige, M., Feige, K., Eikelberg, D., Beineke, A., Metzger, J., Distl, O. :|
|Germline mutation within COL2A1 associated with lethal chondrodysplasia in a polled Holstein family. BMC Genomics 18:762, 2017. Pubmed reference: 29017490. DOI: 10.1186/s12864-017-4153-0.|
|2016||Agerholm, J.S., Menzi, F., McEvoy, F.J., Jagannathan, V., Drögemüller, C. :|
|Lethal chondrodysplasia in a family of Holstein cattle is associated with a de novo splice site variant of COL2A1. BMC Vet Res 12:100, 2016. Pubmed reference: 27296271. DOI: 10.1186/s12917-016-0739-z.|
|2014||Daetwyler, H.D., Capitan, A., Pausch, H., Stothard, P., van Binsbergen, R., Brøndum, R.F., Liao, X., Djari, A., Rodriguez, S.C., Grohs, C., Esquerré, D., Bouchez, O., Rossignol, M.N., Klopp, C., Rocha, D., Fritz, S., Eggen, A., Bowman, P.J., Coote, D., Chamberlain, A.J., Anderson, C., VanTassell, C.P., Hulsegge, I., Goddard, M.E., Guldbrandtsen, B., Lund, M.S., Veerkamp, R.F., Boichard, D.A., Fries, R., Hayes, B.J. :|
|Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle. Nat Genet 46:858-65, 2014. Pubmed reference: 25017103. DOI: 10.1038/ng.3034.|
|2004||Agerholm, JS., Arnbjerg, J., Andersen, O. :|
|Familial chondrodysplasia in Holstein calves. J Vet Diagn Invest 16:293-8, 2004. Pubmed reference: 15305739.|
|1987||Jayo, M.J., Leipold, H.W., Dennis, S.M., Horton, W.H. :|
|Bovine dwarfism: clinical, biochemical, radiological and pathological aspects. Zentralbl Veterinarmed A 34:161-77, 1987. Pubmed reference: 3109166.|
|1978||Jones, T.H., McClintock, A.E., Smith, G.F., Williams, G. :|
|Achondroplasia in British Friesians. Vet Rec 102:404, 1978. Pubmed reference: 664194.|
|1974||Greene, H.J., Leipold, H.W., Huston, K. :|
|Bovine congenital skeletal defects. Zentralbl Veterinarmed A 21:789-96, 1974. Pubmed reference: 4217060.|
|1955||Gotink, W.M., De Groot, T., Stegenga, T. :|
|Erfelijke Gebreken in de Rundveefokkerij. Tijdschr Diergeneeskd 80:1-17, 1955.|
|1948||Berger, J., Innes, J.R. :|
|Bull-dog calves (chondrodystrophy, achondroplasia) in a Friesian herd. Vet Rec 60:57, 1948. Pubmed reference: 18910531.|
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