OMIA 000187-9913 : Chondrodysplasia in Bos taurus

In other species: dog , pig , domestic cat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 225500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2002

Cross-species summary: Abnormal growth of cartilage, leading to disproportionate dwarfism.

Species-specific name: bovine chondrodysplastic dwarfism, bcd

Species-specific symbol: LBN LIMBIN

Species-specific description: Also known as Ellis-van Creveld Syndrome

Mapping: This locus was linkage mapped to the distal end of BTA6 in Japanese Brown cattle by Yoneda et al. (1999). Takeda et al. (2002) refined the region to approximately 2 cM.

By conducting a GWAS on 31,045 informative SNPs genotyped in each of 7 affected and 44 normal Tyrolean Grey cattle, and subsequent homozygosity mapping, Murgiano et al. (2014) mapped this disorder to a 1.6Mb region on chromosome BTA6 that is coincident with the map location in Japanese Brown cattle.

Molecular basis: By sequencing within BAC and YAC contigs covering the candidate region of BTA6, Takeda et al. (2002) identified a new coding sequence containing two mutations that each co-segregate with the disorder in Japanese Brown cattle, namely:

"a C to T transition at position 1356 (C1356T) . . . Remarkably, the C1356T mutation created a cryptic splice donor site in exon 11 (AAGGT1356GAGC) that substituted for the authentic splice donor site and led to improper splicing at position 1355, resulting in the 56-base RNA deletion between 1355 and 1410"; and

"a CA to G substitution at position 2054–2055 (2054–2055delCAinsG) . . . The substitution also caused a frameshift and a premature termination at codon 706, resulting in a 42% shortened protein".

The authors showed clearly that each of these mutations cause the disorder in this breed, i.e. affected calves can be homozygous for either mutant allele or heterozygous for the two mutants.

Takeda et al. (2002) called the newly-identified gene LIMBIN (symbol LBN) because of its association with abnormal limb development. This gene is now called EVC2, because subsequent research suggests that it arose by duplication of the immediately adjacent EVC gene. As explained in the OMIM entry (above), mutations in human EVC and EVC2 cause a similar type of dwarfism in humans [FN 10th Nov 2005; Mohammad Shariflou 7/11/2006; FN 21 Sep 2012]

By whole-genome sequencing of one affected Tyrolean Grey calf, and study of potential missense variants in the candidate region, Murgiano et al. (2014) identified the causal mutation to be "a 2 bp deletion located in exon 19 of the bovine EVC2 gene (c.2993ACdel) . . . The mutation is predicted to cause a frameshift and premature stop codon beginning with amino acid residue 998 in the bovine EVC2 protein sequence (p.Asp998GlufsTer13)". Sanger sequencing and genotyping of other animals in segregating families confirmed this as the causal mutation in this breed.

Breeds: Japanese Black, Tyrolean Grey.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
EVC2 Ellis van Creveld syndrome 2 Bos taurus 6 NC_037333.1 (103497504..103662793) EVC2 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
Japanese Brown Chondrodysplasia EVC2 splicing c.1356C>T 2002 12136126
Japanese Brown Chondrodysplasia EVC2 delins, small (<=20) c.2054_2055delCAinsG 2002 12136126
Tyrolean Grey Chondrodysplasia EVC2 deletion, small (<=20) c.2993_2994delAC p.Asp998GlufsTer13 2014 24733244


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.
2015 Muscatello, L.V., Benazzi, C., Dittmer, K.E., Thompson, K.G., Murgiano, L., Drögemüller, C., Avallone, G., Gentile, A., Edwards, J.F., Piffer, C., Bolcato, M., Brunetti, B. :
Ellis-van Creveld Syndrome in Grey Alpine Cattle: Morphologic, Immunophenotypic, and Molecular Characterization. Vet Pathol 52:957-66, 2015. Pubmed reference: 26077781. DOI: 10.1177/0300985815588610.
2014 Murgiano, L., Jagannathan, V., Benazzi, C., Bolcato, M., Brunetti, B., Muscatello, L.V., Dittmer, K., Piffer, C., Gentile, A., Drögemüller, C. :
Deletion in the EVC2 gene causes chondrodysplastic dwarfism in Tyrolean Grey cattle. PLoS One 9:e94861, 2014. Pubmed reference: 24733244. DOI: 10.1371/journal.pone.0094861.
2003 Mishra, BP., Reecy, JM. :
Mutations in the limbin gene previously associated with dwarfism in Japanese brown cattle are not responsible for dwarfism in the American Angus breed. Anim Genet 34:311-2, 2003. Pubmed reference: 12873227.
Takeda, H., Sugimoto, Y. :
Construction of YAC/BAC contig map for the BTA 6q21 region containing a locus for bovine chondrodysplastic dwarfism Animal Biotechnology 14:51-9, 2003. Pubmed reference: 12887179. DOI: 10.1081/ABIO-120020185.
2002 Takami, M., Yoneda, K., Kobayashi, Y., Moritomo, Y., Kata, S.R., Womack, J.E., Kunieda, T. :
The bovine fibroblast growth factor receptor 3 (FGFR3) gene is not the locus responsible for bovine chondrodysplastic dwarfism in Japanese brown cattle Animal Genetics 33:351-355, 2002. Pubmed reference: 12354143.
Takeda, H., Takami, M., Oguni, T., Tsuji, T., Yoneda, K., Sato, H., Ihara, N., Itoh, T., Kata, S.R., Mishina, Y., Womack, J.E., Moritomo, Y., Sugimoto, Y., Kunieda, T. :
Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism Proceedings of the National Academy of Sciences of the United States of America 99:10549-10554, 2002. Pubmed reference: 12136126. DOI: 10.1073/pnas.152337899.
1999 Yoneda, K., Moritomo, Y., Takami, M., Hirata, S., Kikukawa, Y., Kunieda, T. :
Localization of a locus responsible for the bovine chondrodysplastic dwarfism (bcd) on chromosome 6 Mammalian Genome 10:597-600, 1999. Pubmed reference: 10341093.
1992 Moritomo, Y., Ishibashi, T., Miyamoto, H. :
Morphological Changes of Epiphyseal Plate in the Long Bone of Chondrodysplastic Dwarfism in Japanese Brown Cattle Journal of Veterinary Medical Science 54:453-459, 1992. Pubmed reference: 1643169.
1991 Owen, J.B., Axford, R.F.E. :
Spider and Other Major Genes in Farm Livestock Breeding for Disease Resistance in Farm Animals (eds J.B. Owen and R.F. Axford) chap 25:439-448, 1991.

Edit History

  • Created by Mohammad Shariflou on 07 Nov 2006
  • Changed by Frank Nicholas on 07 Oct 2011
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