Update on CMO Research for Patrick J. Venta, Ph.D

May 2004

CMO (Craniomandibular osteopathy) is an inherited non-cancerous overgrowth of bone primarily occurring in the jaw region of affected dogs, most of whom belong to particular terrier breeds. The disease generally disappears about a year after the initial onset at several months of age. It is rarely fatal, but can cause pain to the puppy and a good deal of distress to the owner. The canine genetics laboratory at Michigan State University is continuing its efforts to identify this gene, so that breeders can identify carriers by a diagnostic test and then make informed breeding decisions to avoid producing affected offspring.

One approach to finding a gene that causes a disease is to test specific candidates genes that are hypothesized to be causative. Candidate genes may be selected because they produce a similar disease in another species, or because their known biological properties suggest that they may be the culprit. Previously, the canine equivalent of a gene that causes a similar bone disorder in humans called Paget’s disease was examined as a candidate gene. Although the data that was developed appeared to exclude this gene it was necessary to be certain that no chromosomal rearrangements had occurred between the human and dog chromosomes harboring this gene that might cause it be falsely excluded. The chromosomal region has now been shown to not be rearranged, and the gene is definitely excluded as being the one that causes CMO.

Reference to this work is currently in press in the scientific journal Genomics. This report also includes a new map of canine chromosome 1 (the largest dog chromosome) that incorporates a large set of a new type of genetic marker called the SNP (pronounced snip, short for single nucleotide polymorphism). This type of marker is likely to make whole genome searches (as opposed to the more directed candidate gene approach) easier and less expensive. The MSU group has made a significant effort to identify SNPs covering all of the canine chromosomes. The support of the AKC Canine Health Foundation and the health branches of the interested breed clubs, including the Westie Foundation of America, The Cairn Terrier Club of America and the Scottish Terrier Club of America, is acknowledged in this report for development of the markers in the CMO region.

The research group has also excluded three more candidate genes, two of these by completely sequencing the protein-encoding portions of these genes in affected dogs. This work was possible because of the recent availability of the raw sequence data from the canine genome-sequencing project being conducted at the Broad Institute, which is associated with the Massachusetts Institute of Technology.

This raw data is currently being assembled at the Broad into a complete map and should be released for public use sometime in June, 2004. This exciting development, in conjunction with the development of a sufficient number of SNP markers to cover the whole dog genome, should make it easier to complete a whole genome scan for the CMO gene if the additional candidate genes currently under study are found not to underlie CMO. Although it is estimated that about 30% of the genome has already been scanned for the CMO gene, the development of the SNPs and the imminent release of the canine genome sequence are very welcome advances. It is likely to have a major impact on the searches not only for the CMO gene, but for genes that lead to other heritable diseases in dogs as well.