DILATED CARDIOMYOPATHY IN PORTUGESE WATER DOGS

葡萄牙水犬的扩张型心肌病

• 批准号: 7391955
• 负责人: PAULA S HENTHORN
• 金额: $ 1.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391955
• 关键词: DILATED; CARDIOMYOPATHY; PORTUGESE; WATER; DOGS

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.

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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。我们已经观察到了12种相关葡萄牙水犬中新型的，早期发作的扩张性心肌病（DCM）。临床健康父母出生的男性和女幼犬通常因充血性心力衰竭而在2-3个月大时死亡。大多数幼犬突然死亡，没有以前的迹象。几只幼犬在死亡前的1-2天有模糊的临床体征。严重地，心脏被严重扩大，并用明显的左心室和心房扩张。没有发现其他结构性心脏缺陷。心脏中的组织学变化是弥漫性的，其特征是薄的肌纤维被膨胀到透明空间的间质分开。肌纤维具有多灶性肿胀段，这通常涉及包含细粒材料的核周区域。没有心肌纤维化或炎症的证据。特定的组织学变化以及疾病的早期发作和快速发展使这是犬DCM的独特形式。对整个狗的其他研究（Sleeper等，2002），其中一个或多个同窝仔受到影响，确认的常染色体隐性遗传遗传，确定的超声心动图改变了先前的充血性心力衰竭，并且没有发现几种代谢参数或心脏蛋白质有时与其他物种相关的几种代谢参数或心脏蛋白质。 该疾病代表了一种潜在的有价值的模型，以增强我们对DCM病理生理学的理解，这对于评估遗传和非遗传性心脏病的疗法可能特别有用。为了捕捉该模型，我们已经在我们的殖民地中杂交了一个育种的杂质性杂合男性，并保留了三个女性后代。私有载体的雄性狗的测试总量已经确定其中一只狗是一名载体女性，并且在她生产的21个后代中产生了4个受影响的后代（其中四个后代不到7个月大，并且可能却可能屈服于该疾病）。这些雌性狗中的一秒钟在2种测试繁殖之后离开了菌落，这表明她不是携带者。第三名雌性产生了11个正常后代，目前已怀孕，很可能（确定性95％）是非携带者的女性。 要充分利用该模型，我们必须了解潜在的遗传缺陷。为此，我们已经开始采用位置候选基因方法来识别所涉及的基因及其突变等位基因。在葡萄牙水犬育种者的合作以及葡萄牙水犬基金会的财政支持下，我们从20只受影响的狗及其亲戚那里收集了DNA（总共有100多只狗）。我们已经启动了整个基因组扫描，作为候选位置基因克隆方法的第一步，以识别负责该疾病的基因和突变。