DILATED CARDIOMYOPATHY IN PORTUGESE WATER DOGS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们在12只相关的葡萄牙水犬中观察到一种新的早发性扩张型心肌病（DCM）。临床上健康的父母所生的雄性和雌性幼犬通常在2-3个月大时死于充血性心力衰竭。大多数幼犬突然死亡，没有先前的体征;少数幼犬在死亡前1-2天有模糊的临床体征。大体上，心脏严重增大和变圆，左心室和心房明显扩张。未发现其他结构性心脏缺陷。心脏的组织学变化是弥漫性的，其特征在于薄肌纤维被扩张到透明空间的结节分开。肌纤维有多灶性肿胀节段，常累及含有细颗粒物质的核周区。没有心肌纤维化或炎症的证据。这种特殊的组织学改变以及疾病的早期发作和快速进展使其成为犬DCM的一种独特形式。其他研究（Sleeper等人，2002），其中一个或多个同窝出生的狗受到影响，证实了常染色体隐性遗传，确定了之前的充血性心力衰竭的超声心动图变化，并发现在其他物种中有时与DCM相关的几个代谢参数或心脏蛋白质没有紊乱。 这种疾病代表了一个潜在的有价值的模型，以提高我们对DCM的病理生理学的理解，这可能是特别有用的遗传性和非遗传性心脏病的治疗评价。为了捕获模型，我们在我们的群体中将一个育种者拥有的专性杂合雄性与一个正常雌性进行了远缘杂交，并保留了三个雌性后代。对私人拥有的携带者雄性狗进行的测试交配已经确定其中一只狗是携带者雌性，并且在她生产的21只后代中产生了4只受影响的后代（其中4只后代不到7个月大，并且可能死于疾病）。第二只雌性犬在2次试验后离开了殖民地，表明她不是携带者。第三只雌性已经产生了11个正常的后代，此时怀孕了，并且很可能（95%确定性）是一只非携带者雌性。 为了充分利用这个模型，我们必须了解潜在的遗传缺陷。为此，我们已经开始了一个位置候选基因的方法，以确定相关的基因及其突变等位基因。在葡萄牙水犬饲养者的合作和葡萄牙水犬基金会的财政支持下，我们收集了20只受影响的狗及其亲属的DNA（总共100多只狗）。我们已经启动了全基因组扫描作为候选位置基因克隆方法的第一步，以确定导致这种疾病的基因和突变。

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.