Increasing DNA marker informativeness in hereditary canine motor neuron disease

遗传性犬脊髓性肌萎缩症（HCSMA）是一种遗传性运动模型， 神经元疾病（MND），与人类MND和其他神经元疾病具有相同的特征。 神经退行性疾病弱点首先出现在HCSMA中，因为 运动神经末梢的突触传递。这种紊乱最终表现为运动性 单位故障，并进展为运动终末变性，运动轴突丢失，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 表明运动神经元活动是进展的主要因素， 这种退化始于运动神经末梢虽然我们知道 关于HCSMA的病理学和细胞生物学，缺陷基因的身份， 仍然未知。先前的研究表明，HCSMA不是由 导致家族性MND的两个最突出的基因（SOD1和SMN）突变， 人类这表明，HCSMA中缺陷基因的鉴定将提供新的 导致MND表型的机制。最近尝试执行 使用低分辨率微卫星标记集的连锁分析未能建立 在HCSMA菌落内存在显著联系。主要问题是， 微卫星标记的多态性不足以产生显著的连锁 信息.可能的原因是大量的近亲繁殖， 在HCSMA殖民地发生的解决这个问题的一个办法是 大大增加了标记的数量。最近发表的犬SNP map及其作为64k微阵列的商业可用性现在使得这种方法 可行我们现在建议对HCSMA的现有DNA进行连锁研究 谱系使用这些新的资源作为第一步，以确定有缺陷的 HCSMA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.