OMIA 002540-9913 : Chondrodysplasia, EVC2-related in Bos taurus

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 225500 (trait) , 607261 (gene)

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.

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

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.

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 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 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 Tyrolean Grey 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.

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.
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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  • Created by Imke Tammen2 on 22 Mar 2022