CMO Project

CMO - Spring 2002 - Update

CMO, a painful bone disease that affects the quality of life of both the affected animal and its owners, usually shows up in animals between the ages of six and twelve months. We know from our disease survey that it affects approximately 15% of the WHWT breed and although we have known for at least twelve years that it was genetically involved, its prevalence in the breed has neither decreased nor increased. Although it is possible to identify carriers of the disease gene by test breeding, this method has many undesirable aspects to it and therefore is not often used. Our research goal is to develop a simple DNA-based test that will allow breeders to identify carrier and homozygous normal animals at any age easily. Our use of this information would allow us to make informed decisions about which animals to use in our breeding programs.

Final Report

Grant No. 1614 Canine Health Foundation
Title: Development of a DNA-Based diagnostic test for cranioman-dibular osteopathy (CMO) of the Cairn Terrier, West Highland White Terrier and Scottish Terrier breeds
Principal Investigator: Patrick J. Venta
Research Institution: Michigan State University

This is the final report based on a two-year study. A third year of research on the same topic has been approved for 2002-2003. The third year’s objective is “to scan reason-ably equally spaced markers across the canine genome within pedigrees segregating for the CMO gene until a linked marker is found.”

The specific objectives of the two-year study were:

(1) To test the hypothesis that the causative gene for CMO is the canine counterpart of the Paget’s disease gene.

Finding: By exclusion analysis, our researchers tested markers for linkage to the Paget’s disease (equivalent of human chromosome 18) and Buchem disease gene (equivalent of human chromosome 17). In both experi-ments, the markers failed to show linkage. Therefore, the researchers have tentatively concluded that the canine equivalents of the Paget’s disease gene and the Buchem disease gene are not causative for CMO in the three breeds studied.

(2) If this hypothesis is rejected, to perform an intelligent, genome wide search for the CMO gene.

Finding: Two recent publications provided data that makes it possible to deduce reasonably which micro-satellite markers are contained in gene-dense regions. The researchers tested markers in the collected CMO DNA samples. They identified, as of the report date, forty SNP (single nucleotide polymorphisms) and based-based markers which showed no linkage to the disease gene. The researchers will continue to evaluate markers that they deduced are in the gene-rich regions and if none of these show linkage, they will proceed to use the markers in the gene-poor regions.

(3) To develop a linkage-based test for carriers of the disease.

Finding: The development of cheek swab-based test for the CMO gene will be pursued in the third-year grant. Dr. Venta has communicated with the other breed clubs as well as our Foundation to determine if it might be best to forego the develop-ment of the linkage-based test so that there will be no delay in the work to proceed to a direct test. It is the desire of our Foundation to produce a linkage-based test and then go to a direct-based test.

Other significant outcomes from this work:

(1) Our researchers developed a method to identify quickly and easily single nucleotide polymorph-isms (SNPs) in or near any canine gene. This is important because this work will eventually allow our researchers to find the actual caus-ative gene and mutation for CMO.

(2) The researchers identified a direct estimate of the inbreeding coefficients of the three breeds using SNPs. They found that inbreeding coefficients were relatively low, indicating that it will be possible to estimate the number of heterozy-gotes in a study population of any size by a progress that we call pool-and type in which a single PCR reaction is performed.

(3) The nearly completed development of an improved map of canine chromosome 7. This is a result of their development of a number of gene-specific markers to test a CMO candidate gene on this chromosome, combined with an unusual coincidence with an unrelated project in the lab that also involved canine chromosome 7.