OMIA 001926-9913 : Achondrogenesis, type II in Bos taurus

Possibly relevant human trait(s) and/or gene(s) (MIM number): 200610

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.

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

Variants

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
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 g.32475732G>A p.G960R 2014 25017103
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
Holstein Bulldog calf COL2A1 missense UMD3.1 g.32476808G>A c.3166G>A p.Gly1056Ser 2019 30378686

References


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.
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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