Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 225500 (trait) , 607261 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Disease-related: 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 Brown, Japan (Cattle) (VBO_0004988), Tiroler Grauvieh (Cattle) (VBO_0000408).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: