Increasing DNA marker informativeness in hereditary canine motor neuron disease

遗传性犬脊髓性肌萎缩症是一种遗传性运动模型 神经元病(MND)与人类MND和其他疾病的共同特征 神经退行性疾病。疲软首先出现在HCSMA中，因为 运动终末的突触传递。这种疾病最终表现为运动障碍。 单位故障并进展为运动神经末梢退化、运动神经轴突丢失，以及 在HCSMA杂合子中，运动神经元丢失最少。我们最近获得的证据 证明运动神经元活动是导致该疾病进展的主要因素。 这种退化从马达终端开始。尽管我们知道的很多 关于HCSMA的病理和细胞生物学，缺陷基因的识别 仍然不为人知。以前的研究表明，HCSMA不是由 引起家族性MND的两个最显著的基因(SOD1和SMN)的突变 人类。这表明，对HCSMA中缺陷基因的鉴定将带来新的 阐明导致MND表型的机制。最近尝试执行的 使用低分辨率微卫星标记集的连锁分析未能建立 在HCSMA群体内有显著的联系。主要的问题是，许多 微卫星标记的多态程度不足以产生显著的连锁 信息。造成这种情况的可能原因是大量的近亲交配 多年来在HCSMA殖民地发生的。这个问题的一个解决方案是 显著增加标记的数量。最近发表了一种犬类SNP MAP及其作为64K微阵列的商业可用性现在实现了这种方法 可行。我们现在建议对来自HCSMA的现有DNA进行连锁研究 使用这些新资源作为识别缺陷者的第一步的谱系 HCSMA中的基因。

Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an inherited model of motor neuron disease (MND) that shares features with human MND and other neurodegenerative diseases. Weakness first appears in HCSMA because of decreased synaptic transmission at motor terminals. The disorder eventually manifests as motor unit failure and progresses to motor terminal degeneration, motor axon loss, and, at least in HCSMA heterozygotes, motor neuron loss. Evidence we have obtained recently demonstrates that motor neuron activity is a major contributing factor to the progression of HCSMA and that degeneration begins at the motor terminal. Although much is known about the pathology and cell biology of HCSMA, the identity of the defective gene remains unknown. Previous studies have shown that HCSMA is not caused by mutations in 2 of the most prominent genes (SOD1 and SMN) that cause familial MND in humans. This shows that identification of the defective gene in HCSMA will shed new light on mechanisms that cause the MND phenotype. Recent attempts to perform linkage analysis using a low resolution microsatellite marker set failed to establish significant linkage within the HCSMA colony. The main problem is that many of the microsatellite markers are not sufficiently polymorphic to yield significant linkage information. The likely cause of this is the extensive amount of inbreeding that has occurred in the HCSMA colony over the years. One solution to this problem would be to dramatically increase the number of markers. The recent publication of a canine SNP map and its commercial availability as a 64k microarray now make this approach feasible. We now propose to perform a linkage study on existing DNA from the HCSMA pedigree using these new resources as a first step towards identification of the defective gene in HCSMA.