Achondrogenesis, type II

Phene ID

3719

Name

Achondrogenesis, type II

Phene Name

Holstein bull-dog dwarfism

OMIA ID

1926

Species ID

9913

Characterised

Yes

Characterised Year

2014

In a remarkable indication of the power of whole-genome sequence analysis, Daetwyler et al. (2014) identified a causal mutation for this disorder in Holstein Friesian cattle as a missense mutation (g.32475732G>A [UMD3.1 reference sequence]; p.Gly960Arg, omia.variant:223) 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 (omia.variant:414): "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, omia.variant:840) in the offspring of a Charolais (sire) x Salers cross; g.32476082G>A (c.2986G>A; p.G996S, omia.variant:841) in a Holstein pedigree; and g.32471813G>A (c.2158G>A; p.G720S, omia.variant:842) 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, omia.variant:1026) 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, omia.variant:1241) 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 COL2A1 (omia.variant:1275) 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).
Jacinto et al. (2025) identified a likely de novo COL2A1 "heterozygous pathogenic 12 bp deletion affecting exon 54 ...(Chr5:g.32312706_32312717del; c.4432_4443del; p.(Gly1478_Ile1481del))" (omia.variant:1835) in a Holstein calf with mild achondrogeneisis.

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. "