MOLECULAR PATHOGENESIS OF FELINE SPINAL MUSCULAR ATROPHY

猫脊髓性肌萎缩症的分子发病机制

• 批准号: 6233658
• 负责人: JOHN C FYFE
• 金额: $ 7.42万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-05 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6233658
• 关键词: animal breeding; animal genetic material tag; autosomal recessive trait; biochemistry; blood tests; cats; degenerative motor system disease; disease /disorder model; disease /disorder onset; electron microscopy; family genetics; genetic disorder; histopathology; immunocytochemistry; linkage mapping; molecular genetics; molecular pathology; motor neurons; neurogenesis; polymerase chain reaction; progressive spinal muscular atrophy; tissue /cell culture

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.

引起中枢神经系统发育异常或退化的遗传缺陷在胎儿和儿童死亡率和发病率中占很大比例。在人类中有许多形式的脊髓性肌萎缩症（SMA），但只有少数已经建立了分子基础。常染色体隐性遗传早发性SMA的常见形式归因于染色体5 q12-q14上运动神经元存活基因（SMN）位点区域的缺陷，是婴儿死亡的主要原因。重度5 q SMA的发生率约为1：10，000，是婴儿最常见的致死性常染色体隐性遗传病，当包括轻度形式时，它是总体上第二常见的儿科神经肌肉疾病。我们已经确定了一个家猫家族，该家族表现出由脊髓运动神经元缺失引起的常染色体隐性形式的SMA，并导致早期青少年发作的骨骼肌萎缩、虚弱和功能丧失。猫疾病在临床上与人类SMA III型不同，代表了人类SMA的一种新的独特动物模型。这项研究的长期目标是表征和使用这种猫模型，以更好地了解正常运动神经元的发育，维持和功能，目的是开发人类脊髓性肌萎缩症的新疗法。该动物模型的表征将满足更好地了解人类运动神经元疾病机制的需求，并可能提供一个测试新治疗方案的系统。我们立即提出了详细描述的疾病的病理，并确定猫SMA的分子遗传基础。这项建议的具体目标是：1）建立并维持SMA猫的繁殖群体，并进行交配，这将为遗传连锁研究提供最多信息，并将为发病机制研究产生额外的受影响和同窝对照，2）表征猫SMA从妊娠晚期至临床体征发作期间疾病进展的组织病理学特征，3）通过检查猫SMA疾病基因座的候选基因来确定猫SMA的分子基础。最初的候选基因将是那些与人SMA有关的基因，但除此之外，将采用比较位置候选基因方法。