Genex bulls tested for Neuropathic Hydrocephalus
Results as of 11/11/09 

Research Update on Hydrocephalus
Jonathan E. Beever, Ph.D.
Earlier this year the American Angus Association, via Dr. Steffen at the University of Nebraska-Lincoln, posted a request for reporting of calves having a phenotype referred to as hydrocephalus. As Dr. Steffen described in the request, these calves have a severe phenotype that includes an extremely large cranium with little or no brain and spinal cord present. Prior to the posting of this request, 15 calves matching this phenotype had been submitted. Since that request, there has been continued reporting of additional calves. It was previously unclear whether the condition had a genetic or environmental basis; however, pedigree analysis of these calves did show common ancestry on both sides of their pedigrees. This was not interpreted as clear evidence of a genetic defect as we believed that this pedigree relationship may have been caused by biased reporting of calves related to pedigrees associated with the arthrogryposis multiplex (AM) defect that had been requested in September 2008.

Using DNA from the reported calves, we performed an analysis in late February 2009 to assess a potential molecular basis of this condition. Based on this analysis, we are able to confirm that this defect is the result of homozygosity at a distinct location on a single cattle chromosome; thus confirming that the condition was caused by a recessive mutation. Since that time, we have continued to investigate this chromosomal region in an effort to identify the specific mutation and develop a DNA-based test to identify carriers of the defect.

We are happy to report that a mutation has been identified that we believe is the cause of this abnormality. This mutation resides within a gene that is involved in development and maintenance of central nervous system tissue. The gene is highly conserved across species as would be expected given its role. Within this gene are several regions that encode parts of the protein with catalytic function. The mutation we have identified is the change of a single DNA base pair. As a result of this change, the encoded protein is also changed at a single amino acid that is highly important in one of these functional regions of the protein. Based on comparison of this change across multiple species from the fruit fly to higher primates, such as humans, this change is classified as "intolerable" or "severely damaging" to protein function. Furthermore, mutations within this gene for species such as the mouse also cause severe abnormalities including high (nearly 100%) embryonic mortality rate.

Similar to the work that was performed for AM, we have had the opportunity to test more than 1,000 DNA samples for this mutation. To date, there have been no living animals identified that are homozygous for this mutation (i.e., have the mutation on both chromosomes). This strongly supports the conclusion that homozygosity for this mutation is incompatible with life and is the causative mutation in this defect. In contrast, all calves that have been diagnosed with this form of hydrocephalus have genotyped as homozygous for this mutation. Additionally, we have identified the common ancestor from which the mutation originated and can confirm that this ancestor is represented on both sides of the pedigrees of all affected calves with DNA samples submitted to date. Therefore, we believe that genotyping individuals for this specific mutation will accurately provide classification regarding this genetic defect.

As we come to the conclusion of this research, we again will be able to provide genotype status on AI sires that were submitted for the AM research. We expect that we will complete the genotyping of these sires by the end of this week and will be ready to release these results in coordination with the American Angus Association and the National Association of Animal Breeders beef committee. In the next couple of weeks we will also aim to move this technology into commercial testing facilities so that at risk animals can be tested.


Neuropathic Hydrocephalus in Beef Cattle

Alfred L. Kuck
Vice President Beef Programs

From the description of Neuropathic Hydrocephalus (NH) by Jonathan Beever, it is clearly evident NH in cattle is the result of a serious mutation. Genex will immediately stop marketing semen from carrier bulls designated as NHC, effective today. Different from the AM mutation, Jonathan Beever thinks he may have found the "origin" animal for this mutation. Since he is very certain of the nature of the mutation and his ability to identify the carriers, we are equally certain the bulls listed as NHF (NH free) in the list do not carry the mutation and can be used with confidence. There are a few bulls that do not have results yet, but they should be available shortly. Genex is continuing to test past active bulls and will report the results as they become available.

If you have recently purchased semen on a Genex sire tested to be a NH carrier, 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 NH results, please see the link above. Remember only half of the offspring from these bulls will be carriers 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.

After a thorough discussion of how to name the mutation, it was felt that the shorter term "Hydrocephalus" did not serve the purpose well, since it can describe a wide range of abnormalities. Thus the name "Neuropathic Hydrocephalus" was thought to be more descriptive. Similar to Arthrogryposis Multiplex, we will probably refer to the syndrome as "NH". The DNA testing designation of "NHF" for NH free and NHC for NH carrier will be simple acronyms for the status of animals.

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