The Immunopathogenesis of Familial Transverse Myelitis Due to Mutations in VPS37a

项目摘要 特发性横肌麻痹（ITM）是一种单一的自身免疫性攻击脊髓，导致虚弱， 麻木和肠/膀胱功能障碍发病率约为每年百万分之1-2， 目前，约有7，500名美国残疾人从他们的ITM中患病。有两个高峰 发病年龄分布在青少年和成年期。男性和女性同样受到影响。 治疗包括在发作时进行免疫抑制，但神经功能障碍持续存在， 超过三分之二的案件。 传统上认为，ITM是一种散发性疾病，没有强的家族危险因素，也没有公认的 基因对风险的贡献最近，我们遇到了一个波兰血统的家庭，他们的两个姐妹篇都受到了ITM的影响， 一个出现在15岁，一个出现在50岁。这一不寻常的事件促使我们寻求一个 基因基础的研究对这对姐妹篇的基因测序显示，她们都携带了一种非常罕见的突变， 在一个基因中，该基因被称为非极性蛋白分选相关蛋白37 A（VPS 37 A）。VPS 37 A是 转运所需的内体分选复合物I（ESCRT-1）复合物，其参与蛋白质的再循环。 这种基因突变在人群中非常罕见，但在86名ITM患者中， 发现了第三名爱尔兰/苏格兰血统的患者，他们携带相同的VPS 37 A基因突变。我们的结果 强烈暗示VPS 37 A在ITM的原因，并表明，家族形式的ITM具有遗传 成分 该提案的目标是了解VPS 37 A中的基因突变如何导致ITM。我们特别 将重点关注这种基因突变如何导致一种倾向，发展免疫介导的攻击， 脊髓

PROJECT SUMMARY Idiopathic transverse myelitis (ITM) is a single autoimmune attack on the spinal cord that leads to weakness, numbness, and bowel/bladder dysfunction. The incidence is approximately 1-2 per million per year with a prevalence of approximately 7,500 Americans living with disability from their ITM today. There is are two peak age distributions with onsets in the teenage years and in adulthood. Men and women are equally affected. Treatment involves immunosuppression at the time of the attack but neurologic disability persists in greater than two thirds of cases. ITM is conventionally viewed as a sporadic disease, with no strong familial risk factors and no recognized genetic contribution to risk. Recently, we encountered a family of Polish origin with two sisters affected by ITM, one presenting at age 15 and one presenting at age 50. This unusual occurrence prompted us to seek a genetic basis for ITM. Genetic sequencing of these sisters revealed that they both harbor a very rare mutation in a gene called Vacuolar Protein Sorting-Associated Protein 37A (VPS37A). VPS37A is a component of the endosomal sorting complex required for transport I (ESCRT-1) complex, which is involved in recycling proteins. This genetic mutation is exceedingly rare in human populations, but among a group 86 ITM patients we discovered a third patient of Irish/Scottish origin who harbored the same VPS37A genetic mutation. Our results strongly implicate VPS37A in the cause of ITM and suggest that familial forms of ITM has a genetic component. The goals of this proposal are to understand how a genetic mutation in VPS37A causes ITM. Specifically, we will focus on how this genetic mutation leads to a predisposition to develop an immune mediated attack of the spinal cord.