CANINE MODELS OF FAMILIAL DILATED CARDIOMYOPATHY

扩张型心肌病(DCM)是一种主要的心肌疾病 以收缩功能障碍和心室扩张为特征的；它 在许多物种中自然发生。(1-3)大约20%的人类DCM 似乎源于家族，这一特征可能是在一个 常染色体(显性或隐性)、X连锁或线粒体 (4，5)家族性扩张型心肌病犬模型也存在。超过50% 被诊断患有DCM的狗中有杜宾犬，它们有近 与人类家族性扩张性心肌病相似。(6-8)金毛猎犬也是 已知患有家族性DCM，有时DCM与 类似Duchenne肌营养不良症(DMD)的肌营养不良 人类。(9-12)除了弥漫性肌萎缩侧索硬化症外，还发现了肌营养不良蛋白异常 在某些情况下。(13-15)我们认为一种家族性的天然动物模型 DCM可以提供机会来研究至少一种DCM的原因 为人类疾病提供了一个候选的基因模型。 患有DCM的杜宾犬和金毛猎犬的系谱已经被 收集的；受影响和未受影响的个体的表型为 特色化的。血液样本也已从受影响的人和 未受影响的家庭成员将淋巴母细胞系发展为 永垂不朽。DNA的来源，并用于DNA分离。那些狗屈服了 将对DCM进行尸检；心肌和骨骼肌样本已经 获取(新鲜冷冻，如有可能，或福尔马林固定)。杜宾犬 从个体中分离出的粉刺和金毛猎犬DNA(血液， 组织)将进行连锁分析以定位染色体基因座 负责DCM和将克隆的区域进行分离和鉴定 在进行突变分析之前确定负责基因。还有，样本 将通过多重聚合酶链式反应和其他方法分析肌营养不良蛋白缺失 突变。这项研究最终将提供一种天然动物 在分子水平和潜在的研究家族性扩张性心肌病的模型 提供一个候选基因(S)用于对这种形式的人类进行评估 心肌病，以及潜在地提高对DCM的认识 DMD和X连锁DCM，人类由于营养不良蛋白异常引起的疾病。

Dilated cardiomyopathy(DCM) is a primary heart muscle disease characterized by systolic dysfunction and ventricular dilatation; it occurs naturally in many species.(1-3) Approximately 20% of human DCM appears to be of familial origin, and the trait may be inherited in an autosomal (dominant or recessive), X-linked, or mitochondrial pattern.(4,5) Canine models of familial DCM also exists. Greater than 50% of dogs diagnosed as having DCM are Doberman pinschers and they have close similarities to familial DCM in humans. (6-8) Golden retrievers are also known to have familial DCM and sometimes have DCM associated with a muscular dystrophy similar to Duchenne muscular dystrophy (DMD) in humans.(9-12) In addition to DCM, dystrophin abnormalities have been shown in some cases. (13-15) We believe that a natural animal model of familial DCM could provide opportunities to study at least one cause of DCM at the molecular level and provide a candidate gene model for human disease. Pedigrees from Doberman pinschers and golden retrievers with DCM have been collected; the phenotypes of affected and unaffected individuals were characterized. Blood samples have also been obtained from affected and unaffected family members to develop lymphoblastoid cell lines as an immortalized.source of DNA, and for DNA isolation. Those dogs succumbing to DCM will be autopsied; cardiac and skeletal muscle samples have been obtained (fresh frozen when possible, or formalin-fixed). Doberman pinscher and golden retriever DNA isolated from individuals (blood, tissue) will be subjected to linkage analysis to map the chromosomal locus responsible for DCM and the region will be cloned to isolate and identify the responsible gene prior to performing mutation analysis. Also, samples will be analyzed for dystrophin deletions by multiplex PCR and other mutations.(16,17) This study will ultimately provide a natural animal model in which to study familial DCM at a molecular level and potentially provide a candidate gene(s) for evaluation in humans with this form of cardiomyopathy, as well as potentially improving the knowledge of DCM in DMD and X-linked DCM, human diseases due to dystrophin abnormalities.(18)