Complex vertebral malformation
Encyclopedia
Complex vertebral malformation or CVM is a lethal hereditary syndrome found in Holstein cattle. CVM is responsible for malformed calves that are either spontaneously aborted or die shortly after birth. It is caused by a missense mutation
in the SLC35A3 gene. Since the mutant form of the gene is recessive
, only individuals carrying two copies of the faulty gene (homozygous individuals) are affected. Heterozygous 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.
for two genetic diseases, CVM and Bovine leukocyte adhesion deficiency
(BLAD). The BLAD and CVM genes are located in different chromosomes. When the sire (father) of Carlin-M Ivanhoe Bell, a bull named Pennstate 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 Pennstate 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.
at position 180 instead of valine
. This causes abnormal nucleotide-sugar transport into the Golgi apparatus
, leading to malformations of the vertebral column
. 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 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 testing.
, 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.
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.
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
in the SLC35A3 gene. Since the mutant form of the gene is recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
, only individuals carrying two copies of the faulty gene (homozygous individuals) are affected. Heterozygous 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 carrierGenetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
for two genetic diseases, CVM and Bovine leukocyte adhesion deficiency
Leukocyte adhesion deficiency
Leukocyte adhesion deficiency , is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. Leukocyte adhesion deficiency is divided into at least two subtypes: LAD1 and LAD2.-Characteristics:...
(BLAD). The BLAD and CVM genes are located in different chromosomes. When the sire (father) of Carlin-M Ivanhoe Bell, a bull named Pennstate 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 Pennstate 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 phenylalaninePhenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
at position 180 instead of valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
. This causes abnormal nucleotide-sugar transport into the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
, leading to malformations of the vertebral column
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
. CVM is the first genetic disorder found to be caused by defects in the SLC35A3 gene. The mutation responsible for CVM is recessively inherited
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
, and heterozygous 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 testing.
Abortions
As many as 88 percent of homozygous, 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, scoliosisScoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
, 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 fertilityFertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
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.