MOLECULAR PATHOGENESIS OF FELINE SPINAL MUSCULAR ATROPHY

导致中枢神经系统异常发育或退化的遗传性缺陷占胎儿和儿童死亡率和发病率的很大比例。人类有多种形式的脊髓性肌萎缩症(SMA)，但只有少数的分子基础得到了证实。常见的常染色体隐性早发性SMA可归因于染色体5q12-q14上运动神经元存活基因(SMN)区域的缺陷，是导致婴儿死亡的主要原因。5q SMA的发病率约为1：10,000，是导致婴儿死亡的最常见的常染色体隐性遗传病，当包括较轻的形式时，它是总体上第二常见的儿科神经肌肉疾病。我们发现了一个家猫家庭，表现为常染色体隐性形式的SMA，由脊髓运动神经元丢失引起，并导致早期幼年发病的骨骼肌萎缩、虚弱和功能丧失。猫的疾病在临床上可与人类的SMA III型区分开来，并代表了一种新的和独特的人类SMA动物模型。这项研究的长期目标是描述和使用这种猫模型，以更好地了解正常运动神经元的发育、维护和功能，目的是开发治疗人类脊髓性肌萎缩的新疗法。这种动物模型的特征将满足更好地了解人类运动神经元疾病机制的需要，并有可能提供一种测试新治疗方案的系统。我们立即提议对这种疾病的病理进行详细的描述，并确定猫科动物SMA的分子遗传学基础。这项建议的具体目的是：1)建立和维持SMA猫的繁育群体，并进行交配，这将为遗传连锁研究提供最大的信息量，并将为发病机制研究产生额外的受影响和产仔对照；2)描述猫SMA从妊娠晚期到临床症状发作的组织病理学特征；3)通过检测候选基因以寻找猫SMA病基因座的证据，以确定猫SMA的分子基础。最初的候选基因将是那些与人类SMA有关的基因，但否则将采取比较位置候选基因的方法。

Inherited defects causing abnormal development or degeneration of the central nervous system comprise a large proportion of fetal and childhood mortality and morbidity. There are many forms of spinal muscular atrophy (SMA) in humans, but for only a few has the molecular basis been established. The common form of autosomal recessive, early-onset SMA is attributed to defects in the region of the survival motor neuron gene (SMN) locus on chromosome 5q12-q14 and is a leading cause of infant mortality. With an incidence of approximately 1:10,000 births, the severe form of 5q SMA is the most common autosomal recessive disease lethal to infants, and when including milder forms, it is the second most common pediatric neuromuscular disorder overall. We have identified a domestic cat family exhibiting an autosomal recessive form of SMA caused by loss of spinal cord motor neurons and resulting in early juvenile-onset skeletal muscle atrophy, weakness, and loss of function. The feline disorder is clinically-distinguishable from SMA type III in humans and represents a new and unique animal model of human SMA. The long-term goals of this investigation are to characterize and use this feline model to better understand normal motor neuron development, maintenance and function, with the objective of developing novel therapeutics for spinal muscular atrophy in humans. Characterization of this animal model will address the need to better understand the mechanisms of motor neuron disease in humans and, potentially, provide a system in which to test new therapeutic protocols. Immediately we proposed to make a detailed description of the pathology of the disorder and to determine the molecular genetic basis of feline SMA. The specific aims of this proposal are: 1) to establish and maintain a breeding colony of SMA cats and to perform matings which will be most informative for genetic linkage studies and will produce additional affected and littermate controls for studies of pathogenesis, 2) to characterize the histopathology of feline SMA as the disorder progresses from late gestation through onset of clinical signs, 3) to determine the molecular basis of feline SMA by examining candidate genes for evidence to the feline SMA disease locus. Initial candidate genes will be those implicated in human SMA, but otherwise a comparative positional-candidate gene approach will be taken.