Complex vertebral malformation or CVM is a lethal hereditary syndrome found in

Holstein cattle Holstein Friesians (often shortened to Holsteins in North America, while the term Friesians is often used in the UK and Ireland) are a breed of dairy cattle that originated in the Dutch provinces of North Holland and Friesland, and Schleswig-Hols ...

. CVM is responsible for malformed calves that are either spontaneously aborted or die shortly after birth. It is caused by a

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

in the SLC35A3 gene. Since the mutant form of the gene is

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

, only individuals carrying two copies of the faulty gene (

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

individuals) are affected.

Heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

individuals, those who carry one copy of the faulty gene and one copy of the normal gene, have no symptoms but may still pass the disease on to their offspring.

Origin

CVM has been traced back to the bull Carlin-M Ivanhoe Bell who lived in the 1980s. He was used for two decades in international Holstein breeding for the exceptional milk production he passed on to his daughters. Unusually, Carlin-M Ivanhoe Bell was a carrier for two genetic diseases, CVM and Bovine

leukocyte adhesion deficiency Leukocyte adhesion deficiency (LAD) is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also kno ...

(BLAD). The BLAD and CVM genes are located in different chromosomes. When the sire (father) of Carlin-M Ivanhoe Bell, a bull named Penstate Ivanhoe Star, was tested he was found to be a carrier of both CVM and BLAD. Carlin-M Ivanhoe Bell's grandsire Osborndale Ivanhoe, however, carried only BLAD. Scientists therefore believe that the mutation responsible for CVM occurred either in Penstate Ivanhoe Starissa, or somewhere in his maternal family. The CVM syndrome was first found in a Danish Holstein stock in 1999, and during the following years it was also found in the United States, United Kingdom, Netherlands, and Japan. Because of the wide international usage of Carlin-M Ivanhoe Bell and the large number of animals descending from him, the CVM gene is found in Holstein cattle throughout the world. By the turn of the 21st century, more than 30 percent of the best Holstein sires in both Denmark and Japan were CVM carriers. A test for CVM was developed in the turn of the 21st century, and was first used in Denmark in 2000.

Effects

CVM is caused by a missense mutation in the bovine SLC35A3 gene. The mutant protein has the amino acid phenylalanine at position 180 instead of

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...

. This causes abnormal nucleotide-sugar transport into the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ...

, leading to malformations of the

vertebral column The vertebral column, also known as the backbone or spine, is part of the axial skeleton. The vertebral column is the defining characteristic of a vertebrate in which the notochord (a flexible rod of uniform composition) found in all chordate ...

. CVM is the first genetic disorder found to be caused by defects in the SLC35A3 gene. The mutation responsible for CVM is recessively inherited, and

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

carriers of the mutation are asymptomatic. CVM analysis found the bovine SLC35A3 to be the first nucleotide-sugar transportation regulating gene also responsible in the formation of vertebrae and ribs. CVM affects foetal development, being a cause of frequent abortions and stillbirths. Affected calves express low birth weight and a variety of malformations in the vertebrae and heart. Diagnose based on just visual examination of a calf may be difficult due to the wide variety in the expression of anomalies, and a definite diagnosis requires

DNA test Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, o ...

ing.

Abortions

As many as 88 percent of

, CVM-affected foetuses are spontaneously aborted within 260 days from the insemination. A normal bovine pregnancy lasts 280 days. Only 4-5 percent of CVM affected foetuses are calved alive. These calves however are nonviable.

Malformations

A CVM affected calf typically has an abnormally short neck and crooked pasterns. Other malformations associated with CVM are malformations or fusing of vertebrae, scoliosis, contraction and crookedness of distal joints, and abnormal shape of head. Hearts of CVM affected calves have been found to have, among other, abnormal placement of main vessels.

Production and breeding

CVM is a cause of multiple problems for a cattle keeper. A CVM carrier cow's

fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...

is 25% lower than normal, and abortions lead to lowered milk production. For these reasons, CVM carriers are often removed. CVM carrier bulls have been pre-eliminated in Europe since the turn of the 21st century. Older bulls were also tested, and some of the best animals were found to be carriers. The removal of this material led to a period of slowing in dairy breeding in a number of European countries.

References

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External links

Morphological variation of "complex vertebral malformation" in Holstein calves

Identification and prevalence of a genetic defect that causes leukocyte adhesion deficiency in Holstein cattle

Complex vertebral malformation in holstein calves
Bovine diseases Genetic animal diseases