This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have observed a novel, early onset form of dilated cardiomyopathy (DCM) in 12 related Portuguese water dogs. Male and female puppies born to clinically healthy parents typically died at 2-3 months of age due to congestive heart failure. The majority of puppies died suddenly without previous signs; a few puppies had vague clinical signs for 1-2 days before death. Grossly, the hearts were severely enlarged and rounded with marked left ventricular and atrial dilation. No other structural cardiac defects were noted. The histologic changes in the hearts were diffuse and characterized by thin myofibers separated by an interstitium expanded to clear space. The myofibers had multifocal swollen segments, which often involved the perinuclear areas that contained fine granular material. There was no evidence of myocardial fibrosis or inflammation. The specific histological changes and the early onset and rapid progression of the disease makes this a unique form of canine DCM. Additional studies (Sleeper et al., 2002) of whole litters of dogs, in which one or more of the littermates was affected, confirmed autosomal recessive inheritance, identified echocardiographic changes the preceded congestive heart failure, and found no derangement of several metabolic parameters or cardiac proteins sometimes associated with DCM in other species. This disease represents a potentially valuable model to enhance our understanding of the pathophysiology of DCM, which may be particularly useful for the evaluation of therapies for inherited and non-inherited heart disease. To capture the model, we have outcrossed a breeder-owned obligate heterozygous male to a normal female in our colony and kept three female offspring. Test matings to privately-owned carrier male dogs have determined that one of the dogs is a carrier female and has produced 4 affected offspring out of 21 she has produced (four of these offspring are less than 7 months old, and may yet succumb to the disease). A second of these female dogs has left the colony following 2 test breedings which indicated she is not a carrier. The third female has produced 11 normal offspring, is pregnant at this time, and is very likely (95% certainty) a non-carrier female. To take full advantage of the model, we must understand the underlying genetic defect. To this end, we have begun a positional candidate gene approach to identify the gene involved and its mutant allele. With the cooperation of Portuguese water dog breeders, and financial support from the Portuguese Water Dog Foundation, we have collected DNA from 20 affected dogs and their relatives (more than 100 dogs in total). We have initiated a whole genome scan as a first step in a candidate positional gene cloning approach to identify the gene and mutation responsible for this disease.
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