OMIA 001340-9913 : Complex vertebral malformation in Bos taurus

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2006

Species-specific name: Haplotype HHC

Species-specific symbol: CVM; HHC

Species-specific description: Complex vertebral malformation is an inherited syndrome in Holstein-Friesian cattle. CVM has been reported in aborted, premature born, stillborn and neonatal calves. Affected calves have a reduced weight, a misshapen backbone and tendon contractions in the legs. Several other malformations including heart malformations are associated with this syndrome. A DNA test is available in Denmark and the Netherlands. [Imke Tammen: 26 Jan 2002] From a study of 62,602 inseminations involving carrier bulls and daughters of carrier bulls, Nielsen et al. (2003) concluded that 77% of affected foetuses are aborted prior to day 260 of gestation, which is the earliest day from which cases have been diagnosed. This means that approximately 3/4 of affected foetuses are not diagnosed by necropsy [FN: 10 Jan 2003]

Mapping: By conducting a genome scan on 7 affected calves and their normal parents, each genotyped for 194 microsatellites, Thomsen et al. (2006) homozygosity-mapped this disorder to around 60cM on chromosome BTA3. Subsequent fine-mapping followed by comparative mapping of BACs containing the most likely candidate markers narrowed the candidate region of around 5.6Mb corresponding to human chromosome HSA1p21.2-21.3, which contains around 20 known or predicted genes.

In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) confirmed the mapping of this disorder to BTA3 at 40-46Mb (UMD 3.0 genome assembly).

Markers: As shown by Fritz et al. (2013), it is very likely that the deleterious haplotypes HH5 and HH6 (which are closely linked to CVM) are reflecting the effect of the causal mutant for this disorder.

Molecular basis: Careful examination of the potential effects of mutations in any of the roughly 20 comparative candidate genes (see Mapping section), followed by mapping and sequencing of the most likely candidate gene, led Thomsen et al. (2006) to discover that CVM is caused by a missense mutation (c.559G>T) leading to V180F in the SLC35A3 gene, which encodes solute carrier family 35, member A3. Subsequent genotyping of this mutation in large numbers of other cattle confirmed that it is causal. (Mohammad Shariflou 11/11/2006; FN 12 June 2013).

Clinical features: Affected animals are either aborted any time during gestation, premature born, stillborn or in rare cases born alive. The weight of the animals is reduced. The defect is characterized by shortening of the cervical and thoracic parts of the vertebral column and symmetrical arthrogryphosis in the front and occasionally in the hind legs. In some cases further abnormalities, including protusion of the tongue, caudventrally displaced ears, protruding abdomen, umbilical hernia, palatochisis, dermoid attached to the conjunctiva, and brachygnathia superior, have been found [Imke Tammen: 26 Jan 2002]

Pathology: The histopathological findings are nonspecific. Radiological findings reveal that the affected calves have anomalies in the vertebral column (mainly cervical and thoracic vertebrae) including hemivertebrae, fused and misshapen vertebrae and ribs, scoliosis and vertebral synostosis. The skull and appendicular skeleton appear to be normal. Cardiac anomalies are reported in aproximately 50 % of the affected calves and involve interventricular septal defects, dextroposition of the aorta, eccentric hypertrophy of the right ventricle, and transposition of the aorta and the truncus pulmonalis [Imke Tammen: 26 Jan 2002]

Prevalence: CVM has so far been reported in Denmark, the USA, the UK and the Netherlands. The defect was traced back to an American AI bull that was formerly used extensively world wide and the prevalence of the disease is expected to be high [Imke Tammen: 26 Jan 2002]

Genetic testing: Cases of CVM studied to date are due to a 559 G>T base substitution in SLC35A3 (solute carrier family 35 member 3). A DNA test is available from the Danish Institute of Agricultural Sciences [Imke Tammen: 26 Jan 2002]. In addition Kanae et al. (2005) developed Polymerase chain reaction-primer introduced restriction analysis (PCR-PIRA) as an alternative method for screening this mutation (Mohammad Shariflou11/11/2006).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
SLC35A3 solute carrier family 35 (UDP-N-acetylglucosamine (UDP-GlcNAc) transporter), member A3 Bos taurus 3 NC_037330.1 (43294662..43248939) SLC35A3 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.

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
Friesian Holstein Complex vertebral malformation SLC35A3 missense UMD3.1 3 g.43412427G>T c.538G>T p.V180F rs438228855 2006 16344554 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Breed information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (https://www.icbf.com/wp/?page_id=2170)

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.
2016 Cole, J.B., Null, D.J., VanRaden, P.M. :
Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility. J Dairy Sci 99:7274-88, 2016. Pubmed reference: 27394947. DOI: 10.3168/jds.2015-10777.
2013 Fritz, S., Capitan, A., Djari, A., Rodriguez, S.C., Barbat, A., Baur, A., Grohs, C., Weiss, B., Boussaha, M., Esquerré, D., Klopp, C., Rocha, D., Boichard, D. :
Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2. PLoS One 8:e65550, 2013. Pubmed reference: 23762392. DOI: 10.1371/journal.pone.0065550.
Ruść, A., Hering, D., Puckowska, P., Barcewicz, M., Kamiński, S. :
Screening of Polish Holstein-Friesian bulls towards eradication of complex vertebral malformation (CVM) carriers. Pol J Vet Sci 16:579-81, 2013. Pubmed reference: 24195298.
2012 Norman, H.D., Miller, R.H., Wright, J.R., Hutchison, J.L., Olson, K.M. :
Factors associated with frequency of abortions recorded through Dairy Herd Improvement test plans. J Dairy Sci 95:4074-84, 2012. Pubmed reference: 22720964. DOI: 10.3168/jds.2011-4998.
Wang, S., Hao, H., Zhao, X., Zhu, H., Du, W., Wang, D., Liu, Y., Qin, T., Wang, Z. :
A rapid mismatch polymerase chain reaction assay to detect carriers of complex vertebral malformation in Holstein cattle. J Vet Diagn Invest 24:568-71, 2012. Pubmed reference: 22529127. DOI: 10.1177/1040638712441605.
2011 Sun, D.X., Fan, X.H., Xie, Y., Chu, Q., Sun, Y., Zhang, Y., Zhang, S.L., Gong, W.J., Chen, S.H., Li, Y.H., Shi, W.H., Zhang, Y. :
Short communication: Distribution of recessive genetic defect carriers in Chinese Holstein. J Dairy Sci 94:5695-8, 2011. Pubmed reference: 22032394. DOI: 10.3168/jds.2011-4345.
VanRaden, P.M., Olson, K.M., Null, D.J., Hutchison, J.L. :
Harmful recessive effects on fertility detected by absence of homozygous haplotypes. J Dairy Sci 94:6153-61, 2011. Pubmed reference: 22118103. DOI: 10.3168/jds.2011-4624.
2010 Meydan, H., Yildiz, MA., Agerholm, JS. :
Screening for bovine leukocyte adhesion deficiency, deficiency of uridine monophosphate synthase, complex vertebral malformation, bovine citrullinaemia, and factor XI deficiency in Holstein cows reared in Turkey. Acta Vet Scand 52:56, 2010. Pubmed reference: 20929557. DOI: 10.1186/1751-0147-52-56.
2008 Schütz, E., Scharfenstein, M., Brenig, B. :
Implication of complex vertebral malformation and bovine leukocyte adhesion deficiency DNA-based testing on disease frequency in the Holstein population. J Dairy Sci 91:4854-9, 2008. Pubmed reference: 19038961. DOI: 10.3168/jds.2008-1154.
2006 Malher, X., Beaudeau, F., Philipot, JM. :
Effects of sire and dam genotype for complex vertebral malformation (CVM) on risk of return-to-service in Holstein dairy cows and heifers. Theriogenology 65:1215-25, 2006. Pubmed reference: 16168472. DOI: 10.1016/j.theriogenology.2005.08.003.
Thomsen, B., Horn, P., Panitz, F., Bendixen, E., Petersen, AH., Holm, LE., Nielsen, VH., Agerholm, JS., Arnbjerg, J., Bendixen, C. :
A missense mutation in the bovine SLC35A3 gene, encoding a UDP-N-acetylglucosamine transporter, causes complex vertebral malformation. Genome Res 16:97-105, 2006. Pubmed reference: 16344554. DOI: 10.1101/gr.3690506.
2005 Kanae, Y., Endoh, D., Nagahata, H., Hayashi, M. :
A method for detecting complex vertebral malformation in Holstein calves using polymerase chain reaction-primer introduced restriction analysis. J Vet Diagn Invest 17:258-62, 2005. Pubmed reference: 15945384.
Kearney, JF., Amer, PR., Villanueva, B. :
Cumulative Discounted Expressions of Sire Genotypes for the Complex Vertebral Malformation and {beta}-Casein Loci in Commercial Dairy Herds. J Dairy Sci 88:4426-4433, 2005. Pubmed reference: 16291634. DOI: 10.3168/jds.S0022-0302(05)73129-5.
2004 Agerholm, JS., Andersen, O., Almskou, MB., Bendixen, C., Arnbjerg, J., Aamand, GP., Nielsen, US., Panitz, F., Petersen, AH. :
Evaluation of the inheritance of the complex vertebral malformation syndrome by breeding studies. Acta Vet Scand 45:133-7, 2004. Pubmed reference: 15663073.
Agerholm, JS., Bendixen, C., Arnbjerg, J., Andersen, O. :
Morphological variation of "complex vertebral malformation" in Holstein calves. J Vet Diagn Invest 16:548-53, 2004. Pubmed reference: 15586570.
Berglund, B., Persson, A., Stålhammar, H. :
Effects of complex vertebral malformation on fertility in Swedish holstein cattle. Acta Vet Scand 45:161-5, 2004. Pubmed reference: 15663076.
2003 Johnson, VS., Ellis, K., Martineau, H., Thompson, H., Barrett, DC. :
Bovine spinal anomaly with anatomical similarities to complex vertebral malformation. Vet Rec 153:598-600, 2003. Pubmed reference: 14640329.
Nielsen, U.S., Aamand, G.P., Andersen, O., Bendixen, C., Nielsen, V.H., Agerholm, J.S. :
Effects of complex vertebral malformation on fertility traits in Holstein cattle Livestock Production Science 79:233-238, 2003.
2002 Nagahata, H., Oota, H., Nitanai, A., Oikawa, S., Higuchi, H., Nakade, T., Kurosawa, T., Morita, M., Ogawa, H. :
Complex vertebral malformation in a stillborn Holstein calf in Japan Journal of Veterinary Medical Science 64:1107-1112, 2002. Pubmed reference: 12520102.
2001 Agerholm, J.S., Bendixen, C., Andersen, O., Arnbjerg, J. :
Complex vertebral malformation in Holstein calves Journal of Veterinary Diagnostic Investigation 13:283-289, 2001. Pubmed reference: 11478598.
Anon. :
Danish scientists reveal the gene responsible for CVM, a lethal heritable defect in Holstein cattle Press release from Danish Cattle Club (http://www.lr.dk/kvaeg/diverse/PRESS-uk.htm, 17 August 2001) :, 2001.
Duncan, R.B., Carrig, C.B., Agerholm, J.S., Bendixen, C. :
Complex vertebral malformation in a Holstein calf: report of a case in the USA Journal of Veterinary Diagnostic Investigation 13:333-336, 2001. Pubmed reference: 11478606.
Revell, S. :
Complex vertebral malformation in a Holstein calf in the UK Veterinary Record 149:659-660, 2001. Pubmed reference: 11764332.
2000 Agerholm, J.S., Bendixen, C., Andersen, O, Arnbjerg, J. :
Report No 564 National Committee on Danish Cattle Husbandry, Aarhus, Denmark :, 2000.
Wouda, W., Visser, I.J., Borst, G.H., Vos, J.H., Zeeuwen, A.A., Peperkamp, N.H. :
Developmental anomalies in aborted and stillborn calves in The Netherlands Veterinary Record 147:612 only, 2000.

Edit History


  • Created by Mohammad Shariflou on 11 Nov 2006
  • Changed by Frank Nicholas on 07 Oct 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 12 Jun 2013
  • Changed by Frank Nicholas on 14 Jun 2013
  • Changed by Frank Nicholas on 18 Jun 2013
  • Changed by Frank Nicholas on 24 Mar 2015