An ongoing objective of the Georgie Project is the study of genetic diseases found in the Portuguese Water Dog population.  These include Canine Hip Dysplasia (CHD), the storage disease GM-1, Cardiomyopathy and to a limited extent PRA.  (Our involvement with PRA is only to the extent that we can supply the Cornell group with pedigree or genetic information and DNA samples from deceased dogs which have participated in the Georgie Project.)
 

Canine Hip Dysplasia (CHD)

We are planning a genetic study of CHD.  CHD is a complex phenotype involving the degree of laxity in the joint between the femur (upper hind leg bone) and the pelvis.  This is clearly seen in this radiograph of a dog in which the joint seen on the viewer's right (dog's left) is dysplastic.

This phenotype is complex, involving the structures of the pelvis and the femur as well as the connective tissue which attaches the two together.
 

GM-1

GM-1 is a glycogen storage disease similar to Tay-Sachs disease in humans.   The genetics and pathology of GM-1 as it exists in the Portuguese Water Dog population have been understood for more than a decade.
 

The Georgie Project took over the task of evaluating the results of GM-1 testing.  The test devised by Alroy was carried out in the Neurology laboatory of Dr. Kalodny at NYU medical school and the results were sent to Utah for evaluation.  In Alroy's original enzymatic test, blood was tested for the relative amount of the enzyme b-galactosidase.  The amount of enzyme activity fell into three groups a normal amount, about half that amount indicating a carrier, or lack of the enzyme typical of the disease.  Nowadays, only two types of individuals are found in the Portuguese Water Dog population: normal or carriers.

Alroy's enzymatic test was indirect and there were certain values that were ambiguous leading to the necessity of retesting.

Fortunately, the NYU group came up with a new, more direct, test: a DNA marker test.  The new DNA test devised by the NYU group is more direct and avoids such ambiguities.  Generally There are two types of DNA tests.  Ones in which the gene itself is directly identified and ones in which the gene is detected by its linkage to another marker.

The GM-1 DNA test can directly identify one or two copies of the GM-1 disease gene.  The Georgie Project has been worked with the NYU group to make sure that the test worked correctly.  From the results, it was clear that the test worked well (100% correct) and that there would not be any ambiguous results.

The development of the new DNA test is an excellent example of how scientists can work well with owners and breeders.  The NYU group is working to develop a therapy for the disease by introducing a healthy gene to replace the function of the defective gene.  If this can work in Portuguese Water Dogs then it will be used for human children:

The Portuguese Water Dog has become an animal model for controlling a human disease and in so doing, a better diagnostic test is born.
 

Cardiomyapathy

Cardiomyapathy has been diagnosed recently in a number of Portuguese Water Dog puppies.  The Georgie Project initiated a study of the genetics of the disease, its ancestry and assisted Dr. Joseph Alroy in his search to find a cure.
 

In analyzing the genetics, it was possible to trace the ancestry of the disease gene:  The details of the pedigrees best support a model in which Taro carried one copy of the recessive disease gene  (Click here for more).

From his own research and from previous work on cats, Joe Alroy determined that the disease involves a nutritional deficiency.

Having developed a physiological assay to determine which puppies were affected in a litter, he determined that the compound, Taurine, was deficient in the blood of these puppies. He then went on to show that supplying Taurine in the diet could restore some of them to health.
 

Dr. Alroy's scientific report on cardiomyapathy is in press and will be published in either October or November 2000 in the American Journal of Medical Genetics under the title "Inherited Infantile Dilated Cardiomyopathy in Dogs: Genetic, Clinical, Biochemical and Morphological Findings".  Currently, Dr. Alroy is trying to develop a test for carriers of the disease gene.
 

Comparison of GM-1 and Cardiomyapathy

It is interesting to compare GM-1 and Cardio.  Both are simple recessive genetic diseases.  Both are lethal before the affecteds can reproduce (unlike PRA).  Yet they appeared at different times in the breed.
 

Using pedigree information and computer simulations, we have analyzed the spread of genes from different PWD ancestors through the population.  On the average, genes from Tabu and Taro have spread at different rates:

Genes from Tabu were introduced earlier into the population than genes from Taro.  The result is that recessive diseases could have appeared earlier.

This is a summary of the the avarage expectation of when a recessive disease, introduced by either of these founders, would appear.  The results are consistant with what we have observed for GM-1 and Cardio.

Addison's disease

Addison's disease occurs frequently in the breed.  It has a complex phenotype and genotype.  Ultimately it is diagnosed as the loss of adrenal function, usually after a rather expensive series of diagnostic tests.

It has a late onset usually between two and ten years of age, which means that a dog with the disease  already may have been bred.  From other breeds and other mammals there is evidence suggesting that the disease may be caused by an autoimmune reaction.  That is, by antibodies produced by a dog against its own adrenal cortex.  The Georgie Project has been active in following all cases of Addison's and recently began a program of necropsy (autopsy) to reveal the true cause of death when a dog has died.  One such autopsy (see the story of Zack) revealed a characteristic syndrome involving an autoimmune syndrome in which a number of glands are attacked.  This syndrome is known in humans as APS (Autoimmune Polyglandular Syndrome).
 

This finding, together with a number of other obvious arguments in favor of autopsy as a means of defining a fatal disease, led to the establishment of the PWD-AAA fund at the University of Utah (click here for details) to finance research into Addisons and related diseases.

The genetics of Addison's are complicated.  Using pedigree information it was possible to calculate the relatedness between all Addisonians.  These were much more closely related than similar groups picked at random from the Portuguese Water Dog population.  However, the number of siblings which do not have the disease is very high.  So high, in fact, that we can rule out a simple recessive or simple dominant mode of inheritance.  The remaining possibilities are much more complex.  All of them try to explain why the actual number of cases is low, compared to what might be expected from simpler modes of inheritance.
 

For example, the number of cases expected will be low if several genes must act together in order to produce the disease.  This is illustrated in this cartoon.  Every time one of the required disease genes is missing, the disease will fail to be inherited.  Parents producing an affected will, between them have the required genes, but more often than not fail to produce an offspring with all present in the right combination.  The "normal" offspring, however, will all continue to spread the bad genes.

Other possibilities involve low penetrance.  The concept of penetrance is that not all conditions of genetic background and/or environmental circumstances (nutrition, excercise regime, infectious disease history, etc.) will allow expression of the disease.
 

Such a circumstance, shown in this cartoon, will result in the failure of a dog which has the disease gene to show the disease until later in life or even not to exhibit the disease in its life time.

One of the important factors in this type of situation is to be able to detect the disease in a sub-clinical stage.  The Georgie Project is beginning a collaboration with Dr. Ed Feldman at UC Davis to try to develop a test which will detect potential Addisonians at an early stage before they develop the disease.

There are two genetic conditions which, with low penetrance, could regulate inheritance of the disease.

The simple recessive-low penetrance model, requires a very high gene frequency in the population, so high that it appears very unlikely that this model is correct.  The simple dominant-low penetrance model is much more compatable with the data and would fit with the known distribution of cases between the two sexes.
 

Much more data is required before we can begin to decide between the simple dominant-low penetrance model and a model of many interacting genes.  Most importantly the results so far emphasize the need for more autopsies on normal as well as affected dogs from litters which contain an affected OR from litters that represent siblings of affecteds (from a repeat mating between parents that already produced at least one addisonian).

Life histories are another important source of information and owners of dogs that are part of an addisonian pedigree might do well to keep a diary on the life of their Portuguese Water Dog.  The time and effort that this requires is more than repaid by the value of this information and the increase in bonding that the owner acquires from such an intimate knowledge of the dog.
 

Immunization history raises an important question:
If Portuguese Water Dogs are genetically predisposed toward autoimmune disease (Georgie's death created a bias toward considering this possibility) then there could be such a thing as too much stimulation of the immune system.  A corollary to this is too much vaccination.

Most vaccines incorporate substances known as adjuvants, which serve as general stimulants of the immune system.  Some of the first adjuvants to be developed were derived from mycobacteria, variants of the Tubercle bacillus.  In humans, there is a predisposition to develop Addison's disease among individuals who have TB.  All of this suggests that exposure to adjuvants may increase the penetrance of this disease.  The Georgie Project plans to explore this further.