OMIA:001926-9913 : Achondrogenesis, type II in Bos taurus (taurine cattle)
In other species: pig
Categories: Skeleton phene (incl. short stature & teeth)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal dominant
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2014
Species-specific name: Holstein bull-dog dwarfism
History: As reported by Agerholm et al. (2001), calves with a bull-dog-like phenotype have been reported in the Holstein breed by Berger and Innes (1948), Gotink et al. (1955), Greene et al. (1974), Jones et al. (1978) and Jayo et al. (1987).
Mapping: On 14 February 2000, in a post to the Angenmap discussion group (http://www.animalgenome.org/community/angenmap/mail/view.php?f=db/1824), Eggen and Boichard reported that this disorder had been mapped (to an undisclosed site) and hence a DNA test (based on linked microsatellites) was available.
Molecular basis: In a remarkable indication of the power of whole-genome sequence analysis, Daetwyler et al. (2014) identified a causal mutation for this disorder as a missense mutation (g.32475732G>A [UMD3.1 reference sequence]; p.Gly960Arg) in the COL2A1 gene (which encodes the alpha-1 chain of type II collagen), by comparing the sequence of only two affected calves with sequence from bulls in the 1000-bull-genome project. Noting that the disorder is most likely dominant, the authors "filtered for heterozygous polymorphisms in the two affected calves that were (i) absent in the 1000 bull genomes project database (except for Igale [the sire of the two affected calves]), as none of the other bulls sequenced had been reported to carry the syndrome and most had been extensively progeny tested, and (ii) predicted modified the amino acid sequence of a protein". This analysis yielded just two candidate mutations, only one of which was in a functional candidate gene, namely COL2A1. The authors then confirmed the causality of this mutation: "Genotyping by PCR and RFLP of the g.32475742G>A mutation in ten additional affected calves showed perfect association between this mutation and the syndrome and suggested mosaicism in the Igale [a Holstein bull] germ line, given the small proportion of affected calves and the fact that affected calves were heterozygous at this position. Finally, Sanger sequencing of the products from conventional PCR and nested PCR performed after PCR and RFLP definitively confirmed mosaicism for Igale at the locus".
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.
Jacinto et al. (2021) reported a "6679 bp deletion includes the entire sequence of 18 exons (26–44) plus the first 36 nucleotides of exon 45" of the COL2A1 gene as being likely causal in "A stillborn purebred Holstein male calf [with] . . . a phenotype resembling the bovine chondrodysplasia type II with the additional presence of perosomus elumbis" (OMIA 000789-9913).
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. "
Charolais (Cattle) (VBO_0000177),
Holstein (black and white) (Cattle) (VBO_0000237).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|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|
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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|
|840||Charolais (Cattle) Salers (Cattle)||Bulldog calf||COL2A1||missense||Naturally occurring variant||ARS-UCD1.2||5||g.32301746G>A||c.1791G>A||p.(G600D)||2017||28904385||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|1275||Holstein (black and white) (Cattle)||Bulldog calf||COL2A1||deletion, gross (>20)||Naturally occurring variant||ARS-UCD1.2||5||g.32301911_32308589del||"Sanger sequencing revealed the precise breakpoints of the heterozygous deletion from position 32 301 911 located in intron 25 to 32 308 589 located within exon 45. The 6679 bp deletion includes the entire sequence of 18 exons (26–44) plus the first 36 nucleotides of exon 45" (Jacinto et al., 2020)||2021||33316082|
|1241||Holstein (black and white) (Cattle)||Bulldog calf||COL2A1||delins, gross (>20)||Naturally occurring variant||ARS-UCD1.2||5||g.32303127_32306640delinsTCTGGGGAGC||2020||32894162|
|842||Holstein (black and white) (Cattle)||Bulldog calf||COL2A1||missense||Naturally occurring variant||ARS-UCD1.2||5||g.32303739G>A||c.2158G>A||p.(G720S)||2017||28904385||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|414||Danish Holstein (Cattle)||bulldog calf||COL2A1||splicing||Naturally occurring variant||ARS-UCD1.2||5||g.32305226G>A||c.2463+1G>A||2016||27296271||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|223||Holstein (black and white) (Cattle)||Bulldog calf||COL2A1||missense||Naturally occurring variant||ARS-UCD1.2||5||g.32307658G>A||p.(G960R)||rs3423194986||2014||25017103|
|841||Holstein (black and white) (Cattle)||Bulldog calf||COL2A1||missense||Naturally occurring variant||ARS-UCD1.2||5||g.32308008G>A||c.2986G>A||p.(G996S)||rs876243579||rs876243579||2017||28904385||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|1026||Holstein (black and white) (Cattle)||Bulldog calf||COL2A1||missense||Naturally occurring variant||ARS-UCD1.2||5||g.32308734G>A||c.3166G>A||p.(G1056S)||2019||30378686|
Cite this entry
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.
|2021||Jacinto, J.G.P., Häfliger, I.M., Gentile, A., Drögemüller, C., Bolcato, M. :|
|A 6.7 kb deletion in the COL2A1 gene in a Holstein calf with achondrogenesis type II and perosomus elumbis. Anim Genet 52:244-245, 2021. Pubmed reference: 33316082 . DOI: 10.1111/age.13033.|
|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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