Understanding the Role of Somatic Mutations in Adult Inflammatory Diseases

了解体细胞突变在成人炎症性疾病中的作用

• 批准号: 10512803
• 负责人: David Beck
• 金额: $ 24.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512803
• 关键词: Adrenal Cortex Hormones; Adult; Affect; Appearance; Arthralgia; Cell Culture Techniques; Cell Survival; Cells; Characteristics; Clinical; Codon Nucleotides; Data; Development; Diagnosis; Disease; Dose; Dysmyelopoietic Syndromes; Enzymes; Failure; Fever; Genes; Genetic; Genetic Diseases; Genetic Polymorphism; Genotype; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Individual; Inflammation; Inflammatory; Interferon-alpha; Interleukin-6; Lead; Life; Link; Lung; Lymphoid; Lymphoid Cell; Missense Mutation; Modeling; Molecular; Molecular Diagnosis; Mosaicism; Mutation; Myelogenous; Myeloid Cells; NF-kappa B; Names; Onset of illness; Pathogenesis; Pathway interactions; Patient Care; Patients; Penetrance; Plasma Cell Neoplasm; Polyarteritis Nodosa; Prevalence; Protein Isoforms; Proteins; Public Health; Relapsing polychondritis; Rheumatism; Role; Signal Transduction; Somatic Mutation; Syndrome; Temporal Arteritis; Testing; Toxic effect; Translations; Ubiquitin; Up-Regulation; Vacuole; Validation; Variant; Work; autoinflammatory; base; clinical care; clinical phenotype; cohort; cytokine; effective therapy; genetic analysis; genetic approach; genetic variant; improved; insight; loss of function; men; middle age; mutant; novel; patient stratification; peripheral blood; pleiotropism; precursor cell; response; risk stratification; skin lesion; standard of care; transcriptomics

Inflammatory rheumatologic diseases affect millions of individuals and represent a significant public health burden. Considerable progress has been made in understanding the molecular basis of rheumatic disease, but molecular diagnoses and mechanistic insights into the causes of adult-onset disease are incomplete. In addition, although there are many effective treatments, a significant percentage of patients remains poorly controlled on current standard of care therapies. It is therefore crucial to improve our understanding of the molecular signaling underlying these life-threatening diseases, which in turn will lead to more effective treatments. To date, a wealth of genetic data has identified common polymorphisms associated with rheumatologic diseases, however very few causative and targetable variants have been identified. We have performed a genotype-first analysis looking for mutations in genes in the ubiquitin pathway in our cohort of patients with undiagnosed inflammatory disorders and have identified affected individuals who share somatic, missense mutations in the UBA1 gene at the same codon, p.Met41 (Beck DB et al, NEJM). All of these individuals have overlapping disease manifestations, including fevers, pulmonary infiltrates, skin lesions, arthralgias, peripheral blood counts concerning for hematologic malignancy, characteristic vacuolization of hematopoietic precursor cells, and a failure to respond to any therapy other than high dose corticosteroids. We have named this disease VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory Somatic) syndrome. Patients with VEXAS syndrome meet clinical criteria for seemingly disparate inflammatory (relapsing polychondritis, polyarteritis nodosa, giant cell arteritis) and hematologic (myelodysplastic syndrome or plasma cell dyscrasias) conditions. UBA1 p.Met41 mutations are restricted to the myeloid lineage, primarily absent from lymphoid lineages, and cause severe inflammatory disease. Furthermore, we have identified that mutations in UBA1 at p.Met41 lead to altered protein isoform expression and translation of a toxic isoform. In the work proposed here, I will study how mosaic mutations in myeloid cells result in aberrant myeloid and lymphoid lineage development and inflammation at the cellular and molecular level (Aim 1). I will then characterize the prevalence and penetrance of UBA1 mutations and find additional genetic causes of other late-onset inflammatory diagnoses (Aim 2). Based on our current findings, I hypothesize that somatic variants are an overlooked cause of many severe, adult-onset inflammatory diseases. Our results with VEXAS syndrome demonstrate that by analyzing genetic variants in a broad spectrum of severe inflammatory diseases we can uncover common underlying mechanisms of pathogenesis which may reveal clinically important reclassifications of disease and ultimately lead to improved clinical care.

炎症性风湿病影响数百万人，是一个重要的公共卫生问题 负担在了解风湿性疾病的分子基础方面已经取得了相当大的进展，但 对成人发病原因的分子诊断和机理认识尚不完整。此外，本发明还提供了一种方法， 虽然有许多有效的治疗方法，但仍有相当比例的患者对药物控制不佳。 目前的标准治疗。因此，提高我们对分子信号传导的理解至关重要。 这些威胁生命的疾病的基础，这反过来又会导致更有效的治疗。迄今为止， 的遗传数据已经确定了与风湿病相关的常见多态性，然而， 已查明的致病和可针对的变异很少。 我们进行了基因型优先的分析，在我们的队列中寻找泛素途径的基因突变 患有未确诊的炎症性疾病的患者，并已确定受影响的个体， 在相同密码子p.Met41处的UBA1基因中的错义突变（Beck DB等人，NEJM）。所有这些人 有重叠的疾病表现，包括发热、肺浸润、皮肤病变、关节痛， 外周血细胞计数与恶性血液病有关，造血细胞空泡化特征 前体细胞，以及对除高剂量皮质类固醇外的任何治疗均无反应。我们命名 这种疾病VEXAS（E1酶，X连锁，自体炎性体细胞）综合征。患者 VEXAS综合征符合看似不同的炎性（复发性多囊炎， 结节性多动脉炎、巨细胞动脉炎）和血液学（骨髓增生异常综合征或浆细胞恶液质） 条件UBA1 p.Met41突变仅限于髓系，主要不存在于淋巴系。 血统，并导致严重的炎症性疾病。此外，我们已经确定UBA 1的突变， p.Met41导致改变的蛋白质同种型表达和毒性同种型的翻译。在这里提出的工作中， 我将研究骨髓细胞的嵌合突变如何导致异常的骨髓和淋巴谱系发育 以及细胞和分子水平的炎症（目标1）。然后，我将描述患病率， 排除UBA1突变并发现其他迟发性炎症诊断的其他遗传原因 (Aim 2）的情况。根据我们目前的发现，我假设体细胞变异是许多被忽视的原因。 严重的成人炎性疾病我们对VEXAS综合征的研究结果表明， 在广泛的严重炎症性疾病的遗传变异，我们可以发现共同的潜在的 发病机制，可能揭示临床上重要的疾病重新分类， 从而改善临床护理。