Duplication with the authorization of the Institut Fur Genetik.
New DNA test for craniomandibular osteopathy (CMO)
in three Scottish terrier breeds (December 1st, 2012)
Craniomandibular osteopathy (CMO) is a non-neoplastic (not a tumor),
proliferative disease altering form and function of the bones of the skull (tympanic
bullae) and jaw bone (mandible). This disease is known by several synonyms,
such as ‘mandibular periostitis’, ‘Westie jaw’, ‘Scottie jaw’ and ‘lion’s
The CMO disease was first recognized in England more than 50 years ago and
since that time CMO is suspected to be inherited as monogenic trait. The
disease predominates in Cairn terriers, Scottish terriers, and West Highland
White terriers and rarely in other breeds of dogs.
The disease is seldom recognized until signs of discomfort during chewing
and eating are observed.
This usually occurs when the dogs are from 4 to 7 months old. The jaw is
bilaterally thickened and several bones become so large and tender that the
mouth cannot be fully opened. The tenderness of the affected jaw is
associated with intermittent fever of 3 or 4 days duration. This tenderness
and fever may recur every 2 to 4 weeks during the bony proliferation phase.
Radiography is the best method for diagnosing CMO. Treatment is symptomatic.
Most animals can be made comfortable using corticosteroids. However,
treatment does not result in cure. Although the primary disease process does
not seem to cause death, in some cases euthanasia has been performed because
pain and malnutrition resulting from the inability to eat.
At the Institute of Genetics, Vetsuisse faculty, University of Bern,
Switzerland, and the Department of Veterinary Biosciences and Research
Programs Unit, Molecular Medicine, University of Helsinki and Folkhälsan
ter, Finland, we have investigated the genetics of CMO in Cairn, Scottish,
and West Highland White terriers. In our initial experiments we performed a
genome-wide association study using DNA from 10 CMO affected dogs (cases)
and 41 unaffected (control) dogs of West Highland White terriers. This
approach enabled us to map the causative mutation to a small region of the
genome on dog chromosome 5. Further experiments revealed that at least one,
mostly two copies
of the CMO associated chromosome 5 segment was present in all CMO cases of
Cairn, Scottish, and West Highland White terriers.
In a second round of experiments we sequenced the whole genome of a CMO
affected West Highland White terrier. Our detailed analysis uncovered a
single causal DNA mutation for CMO. This mutation alters the coding part of
a single gene, and leads to the expression of a defective protein.
The mutation was investigated in a total of 75 cases and 400 controls and
found to be very highly associated with CMO in all three affected terrier
Out of the 75 CMO affected dogs in our sample collection 63 had two copies
of the mutation (84%). Of the remaining twelve dogs, ten had a single copy
of the mutation (heterozygous), which can be explained with CMO being an
incompletely penetrant autosomally dominant inherited disease.
Because of incomplete penetrance and varying expressivity, many of the dogs
carrying the CMO mutation will live without showing clinical signs. We also
tested dogs of all three terrier breeds without reported CMO signs and we
observed all three possible genotypes. Within a cohort of 303 West Highland
White terriers the frequency of the mutant allele was 36%. These presumed
healthy dogs carrying one or two copies of the mutation are used for
breeding, whereby the disorder may be perpetuated. We noticed that two CMO
diagnosed dogs did not carry the mutation. These dogs possibly represent
misdiagnosed cases or are affected due to other unknown genetic or non-genetic
Dogs that are homozygous mutant (two copies of the mutation) have a
comparably higher risk to develop CMO. Dogs heterozygous for the mutation
(one copy of the mutation) might also develop clinical signs; they are
classified at low risk. However, at the moment we don’t have a sufficient
number of CMO diagnosed dogs to give exact penetrance levels (probability to
develop the disease) for the homozygous and heterozygous genotypes,
respectively. Furthermore, we have no evidence that the individual severity
of the disease is related to the genotype (variable expressivity in dogs
with one or two copies of the mutation). The development of the CMO disease
is dependent on the genotype but obviously influenced by other unknown
genetic and/or non-genetic (environmental) factors. The mutation that we
have identified may work in conjunction with unknown ‘modifier’ mutations in
the three studied dog breeds. These modifier mutations would be harmless on
its own, but are disease-exacerbating when inherited along with the CMO
mutation. We speculate that the modifier mutations are quite common, and it
is therefore rare for dogs to have two copies of the CMO mutation and to be
free of the modifier mutation, and as a result, to be clinically free from
The results of our research suggest that there may be other causes of CMO in
the breeds so we cannot exclude the formal possibility that carriers could
develop a genetically different form of CMO due to other mutations that are
not detected by this test.
The test will be based on the CMO causing mutation we have identified and
will accurately provide the genotype of Cairn terriers, Scottish terriers,
and West Highland White terriers. Results will be explained as follows:
These dogs have two normal copies of DNA and are highly likely to be clear
CMO-1 (low risk): These dogs have one copy of the CMO mutation and one normal copy of DNA.
These dogs are at low risk to develop CMO themselves as a result of the CMO
mutation and they will pass the mutation on to approximately 50% of their
offspring. The other 50% of their offspring will receive a normal copy of
the gene. If these animals are bred with a clear (CMO-0) partner, half of
the puppies will be CMO-1 (low risk), the other half will be CMO-0 (clear).
CMO-2 (high risk): These dogs have two copies of the CMO mutation and have a high chance of
developing CMO (more than 57 % of dogs studied in our research program with
two copies of the CMO mutation were clinically affected with CMO).
Veterinarians and breeders should be aware that the CMO-2 genotype is not
completely penetrant. CMO-2 dogs will transmit one copy of the mutant
gene to all their offspring.
The test will effectively reduce the number of CMO cases in the affected
three terrier breeds. We strongly discourage to breed with CMO-2 dogs. CMO-1
dogs may be still used in breeding, if they are mated with homozygous CMO-0
(clear) dogs. A strict exclusion of all CMO-1 dogs would narrow the
restricted gene pool of the affected breeds too much. This might lead to an
increase of other
hereditary diseases. Valuable CMO-1 breeding dogs should be used at the
moment and will have 50% free offspring, if they are mated to CMO-0 animals.
The free offspring can then be used to select the best dogs with the desired
traits for the next generation.
We particularly encourage owners of clinically affected dogs to submit
samples. Blood samples from affected dogs that are submitted together with
the X-rays, will be tested free of charge. This information will help us to
evaluate the penetrance level of the mutation, to possibly refine the risk
prediction in the future if necessary and to start to investigate possible
additional cause(s) of CMO in
the three terrier breeds.
We would like to thank all individuals who have contributed to this research
and to all the dog owners and breeders who have contributed blood samples
and information to this research.