The Immunopathogenesis of Familial Transverse Myelitis Due to Mutations in VPS37a

VPS37a 突变引起的家族性横贯性脊髓炎的免疫发病机制

• 批准号: 10658427
• 负责人: Michael Levy
• 金额: $ 41.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658427
• 关键词: Adult; Affect; Age; Age Distribution; American; Antigens; Autophagocytosis; Biological Markers; Bladder Dysfunction; Cell Culture Techniques; Cells; Central Nervous System; Circulation; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Complex; DNA; DNA Sequence Alteration; Disease; Endosomes; Family; Future; Genes; Genetic; Genetic Models; Goals; Human; Image; Immune; Immune response; Immune signaling; Immune system; Immunosuppression; Incidence; Inflammatory; Integral Membrane Protein; Intestines; Link; Lipids; Lymphocyte; Mass Spectrum Analysis; Mediating; Medical; Membrane Proteins; Modality; Molecular Mimicry; Multivesicular Body; Mutation; Nervous System; Nervous System Physiology; Neurologic; Neurons; Numbness; Paralysed; Pathogenesis; Pathway interactions; Patients; Peptide Sequence Determination; Peripheral; Persons; Polishes; Population; Predisposition; Prevalence; Production; Proteins; RNA; Recording of previous events; Recycling; Research; Risk; Risk Factors; Role; Serology; Signal Pathway; Sister; Sorting; Spinal Cord; System; Systemic infection; Teenagers; Testing; Time; Transverse Myelitis; Vacuolar Protein Sorting; Variant; Vesicle; Woman; Work; autoimmune pathogenesis; biobank; disability; exome sequencing; exosome; experimental study; extracellular vesicles; genetic variant; granulocyte; insight; men; meter; monocyte; neuron component; novel therapeutics; osteosarcoma; treatment response

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.

项目概要 特发性横贯性脊髓炎 (ITM) 是一种针对脊髓的单一自身免疫性攻击，会导致无力、 麻木和肠/膀胱功能障碍。每年发病率约为百万分之 1-2 目前，大约 7,500 名美国人患有 ITM 残疾。有两个峰值 发病年龄分布在青少年时期和成年期。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，但神经功能障碍在更大范围内持续存在 超过三分之二的案例。 ITM 通常被认为是一种散发性疾病，没有强烈的家族危险因素，也没有得到公认 遗传对风险的贡献。最近，我们遇到一个波兰裔家庭，有两个姐妹受到ITM影响， 一名在 15 岁时就诊，一名在 50 岁时就诊。这种不寻常的现象促使我们寻找一种 ITM 的遗传基础。这些姐妹的基因测序显示她们都携带一种非常罕见的突变 位于称为液泡蛋白分选相关蛋白 37A (VPS37A) 的基因中。 VPS37A 是一个组件 转运 I (ESCRT-1) 复合物所需的内体分选复合物，该复合物参与蛋白质的回收。 这种基因突变在人群中极其罕见，但在 86 名 ITM 患者中，我们发现 发现了第三名爱尔兰/苏格兰血统的患者，其携带相同的 VPS37A 基因突变。我们的成果 强烈暗示 VPS37A 与 ITM 的病因有关，并表明 ITM 的家族形式具有遗传性 成分。 该提案的目标是了解 VPS37A 的基因突变如何导致 ITM。具体来说，我们 将重点关注这种基因突变如何导致对免疫介导的攻击产生倾向 脊髓。