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: 6530558
• 负责人: JOHN C FYFE
• 金额: $ 7.44万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530558
• 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.

导致中枢神经系统异常发育或变性的遗传缺陷构成了很大一部分胎儿和儿童的死亡率和发病率。人类中有多种形式的脊柱肌肉萎缩（SMA），但仅建立了分子基础。常染色体隐性，早发SMA的常见形式归因于5q12-Q14染色体上的生存运动神经元基因（SMN）基因座的缺陷，并且是婴儿死亡率的主要原因。 5Q SMA的严重形式的发生率约为1：10,000，是婴儿最常见的常染色体隐性疾病杀伤力，当包括温和的形式时，它是第二个最常见的小儿神经肌肉疾病。我们已经确定了一个家庭猫家族，该家族表现出由脊髓运动神经元丧失引起的常染色体隐性形式的SMA，并导致早期少年发作的骨骼肌肉萎缩，无力和功能丧失。猫疾病与人类的SMA III临床区分可与人类III造成区分，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科动物模型来更好地了解正常运动神经元的发展，维护和功能，目的是为人类的脊柱肌肉萎缩开发新的治疗剂。该动物模型的表征将解决人们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。我们立即提议对疾病的病理进行详细描述，并确定猫SMA的分子遗传基础。 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为了证明猫SMA疾病基因座。最初的候选基因将是与人类SMA有关的基因，但否则将采用比较的位置候选基因方法。

项目成果

Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy.

在脊髓性肌萎缩的猫模型中，下运动神经元径向生长的失败先于逆行性变性。

• DOI: 10.1002/cne.23010
• 发表时间: 2012
• 期刊: The Journal of comparative neurology
• 作者: Wakeling,ErinN;Joussemet,Béatrice;Costiou,Patrick;Fanuel,Dominique;Moullier,Philippe;Barkats,Martine;Fyfe,JohnC
• 通讯作者: Fyfe,JohnC