Osteopetrosis Results on Genex Sires

Osteopetrosis "Marble Bone Disease" Update

Researchers find Causal Mutation
A collaborative effort of scientists at USDA MARC, USDA BARC, University of Illinois, University of Nebraska-Lincoln, University of Maryland and University of Wyoming has identified a mutation causing Osteopetrosis (OS) in Red Angus cattle. They used the recently developed Bovine SNP50 or "50K" chip that was important to the success and speed of the project. The disease is caused by a mutation in a gene necessary for bone remodeling during development, known as SLC4A2. Mutations in this gene have also been shown to cause OS in a mouse model, reported in the February issue of the Proceedings of the National Academy of Science.

Using breeder reports on OS affected calves as well as DNA samples obtained from these calves and many of their parents; the team was able to determine that part of the SLC4A2 gene is missing in both copies of bovine chromosome number 4 in the OS calves.

A DNA test capable of identifying carriers of this defect has been developed and will become commercially available in the next 30 to 45 days. The test has undergone several optimizations that have led us to believe that it is highly reproducible and accurate. However, as with any task requiring human intervention, errors can occur. Of course, we do our best to limit any errors that occur by automating portions of the test and appropriate incorporation of testing controls.

As part of test development, we have been able to provide the genotypes and OS status of many A.I. sires. These sires were used as an essential part of our research for three purposes. First, a broad cross section of genetics representing the Red Angus breed is necessary to assess the validity of any diagnostic test that is developed. This assessment is based on the principle that because OS is a lethal abnormality with an assumed recessive mode of inheritance, there should not be any living animals that are homozygous for the mutation. Second, if our assessment is correct and we have identified the mutation that causes OS, then the results of testing would provide genotype information for all of the sires used in this analysis. This allows breeders to assess the genetic risk of their breeding programs and prepare for implementation of future testing programs. Third, this sampling provides an overall assessment of the frequency of the mutation within the entire Red Angus population.

The naming scheme chosen to use for this test identifies animals as having one of three possible genotypes. If an animal is homozygous for the normal variant (called an allele) we refer to them as OS-Free (OSF) indicating they have been tested for the causative mutation and been found to be "free" of the mutation. Therefore these animals are unable to transmit it to any of their offspring. If an individual is tested and found to be heterozygous or a "carrier" of the mutation, meaning they possess one normal allele and one mutant allele, they are referred to as OS-Carrier (OSC). These animals pass the mutation onto approximately half of their offspring. Although affected calves are rarely tested, they would be homozygous for the mutation and referred to as OS-Affected (OSA). This nomenclature is based on several concepts. First, the term used should have relevance to the more technical aspects of the disease, particularly for veterinary professionals who might encounter the condition as part of their practice. In these instances, if they are unfamiliar with the condition it is more likely that they will investigate it using the medical descriptors and not common terminology. Second, there is a precedent for describing these recessives that has scientific merit and is already in place within other organizations.

In regard to the accuracy of the test, there are two distinct components that contribute to how the DNA test performs. The first component involves the scientific data that underlie the test. The second component is the design and execution of the diagnostic assay performed as part of the testing procedure. From a scientific standpoint, the OS test is based on the presence of a specific change or mutation in the DNA sequence of specific genes of an animal. For OS, this change is deletion of a segment of DNA that includes portions of a gene (a gene is a sequence in the DNA that encodes a protein) that has been shown to be involved in bone development. This mutation results in no protein being produced from this gene and therefore it is unable to carry out its normal function, referred to as a loss-of-function mutation. After identifying the specific mutation, experiments were conducted to validate the relationship between the mutation and OS.

Based on these experiments, we believe that the scientific basis of the test is accurate; in other words, testing for this specific mutation will lead to correct classification of Red Angus animals. However, it remains unclear as to the utility of this diagnostic in black Angus animals even given the ancestral relationship between the Red Angus and black Angus breeds.

Description:
Calves are born prematurely (10-30 days premature). Typically calves are born dead, but if born alive will die within 24 hours after birth. Calves possess a short lower jaw and impacted molars. Long bones are fragile and can be broken with ease.


Osteopetrosis in Beef Cattle
Alfred L. Kuck, Vice President Beef Programs

From the description of Osteopetrosis, it is clearly evident that OS in cattle is the result of a serious mutation. At this point all sires in the Genex active lineup are OSF, they do not carry the mutation and can be used with confidence. Genex is continuing to test previously active bulls and will report the results as they become available.

Currently there is one previously active bull which has tested OSC. If you have purchased semen in the last 30 months on this sire, Genex will issue a credit on your account for these units. Contact your local representative to initiate this process and for instructions on returning the semen. Genex will not replace semen that has been used already, and resulting calves will be eligible for registry in most breed associations. For a current list of active and previously active Genex sires and their OS results, please see the link above. Remember only half of the offspring from carrier bulls will be carriers themselves and an affected calf will occur only one in four times when two carriers are mated to each other. If any effort has been made to avoid inbreeding, we would not expect to have any affected calves on these sires.

If you have any questions concerning this recessive and its manifestations, don't hesitate to contact the Genex beef department.