OMIA:002540-9913 : Chondrodysplasia, EVC2-related in Bos taurus (taurine cattle)
Categories: Skeleton phene (incl. short stature & teeth)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2002
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 (follow hyperlink 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.
Japanese Brown, Japan (Cattle) (VBO_0004988),
Tiroler Grauvieh (Cattle) (VBO_0000408).
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|
|EVC2||Ellis van Creveld syndrome 2||Bos taurus||6||NC_037333.1 (103497473..103662789)||EVC2||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|
|375||Japanese Brown, Japan (Cattle)||Chondrodysplasia||EVC2||splicing||Naturally occurring variant||ARS-UCD1.2||6||g.103594013C>T||c.1356C>T||Variant creates a cryptic splice donor site in exon 11 which is leading to improper splicing at position c.1355 and resulting in the 56-base RNA deletion between 1355 and 1410. The deletion causes a frameshift and premature termination.||2002||12136126||The genomic location on ARS-UCD1.2 was determined by Katie Eager and Shernae Woolley, EMAI, NSW. Department of Primary Industries.|
|617||Japanese Brown, Japan (Cattle)||Chondrodysplasia||EVC2||delins, small (<=20)||Naturally occurring variant||ARS-UCD1.2||6||g.103609778_103609779delinsG||c.2327_2328delinsG||p.(A776Gfs*22)||Published as c.2054_2055delCAinsG, cDNA and protein position in this table based on ENSBTAT00000005613.6||2002||12136126||The genomic location on ARS-UCD1.2 was determined by Katie Eager and Shernae Woolley, EMAI, NSW. Department of Primary Industries.|
|534||Tiroler Grauvieh (Cattle)||Chondrodysplasia||EVC2||deletion, small (<=20)||Naturally occurring variant||ARS-UCD1.2||6||g.103651709_103651710del||c.2993_2994del||p.(D998Efs*13)||2014||24733244||The genomic location on ARS-UCD1.2 was determined by Katie Eager and Shernae Woolley, EMAI, NSW. Department of Primary Industries. 210909 FN: given that the variant is a 2bp del (AC), g.103651710_103651710del needs to be changed. BLASTing with AGAGGAGCAAGAAGAC from Fig.4 indicates that it is 719 and 710 that are deleted. THus the entry is changed to g.103651709_103651710del; and AC is removed from the c. entry.|
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.
|2023||Matsumoto, H., Kimura, S., Saito, R., Takeichi, M., Kashimura, A., Inenaga, T. :|
|Causative alleles for chondrodysplastic dwarfism, factor XI deficiency, and factor XIII deficiency in the Kumamoto sub-breed of Japanese Brown cattle. Anim Sci J 94:e13882, 2023. Pubmed reference: 37909240 . DOI: 10.1111/asj.13882.|
|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 .|
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