Understanding the Role of Somatic Mutations in Adult Inflammatory Diseases

炎症性风湿病影响着数百万人，并代表着重大的公共健康 负担。在了解风湿病的分子基础方面已经取得了相当大的进展，但 分子诊断和对成人发病原因的机械性洞察是不完整的。此外, 虽然有许多有效的治疗方法，但相当大比例的患者仍然控制不佳。 目前的护理治疗标准。因此，提高我们对分子信号的理解是至关重要的。 这些危及生命的疾病的潜在危险，这反过来将导致更有效的治疗。到目前为止，一笔财富 的遗传数据已经确定了与风湿病相关的常见多态，然而 几乎没有发现有致病和靶向的变异。 我们在我们的队列中进行了一项基因优先分析，寻找泛素途径基因的突变。 未确诊的炎症性疾病患者，并已确定受影响的个体具有相同的躯体， UBA1基因在相同密码子p.Met41处的错义突变(Beck DB等人，NEJM)。所有这些人 有重叠的疾病表现，包括发热、肺部浸润性病变、皮损、关节痛、 外周血计数与恶性血液病、造血细胞特征性空泡化有关 前体细胞，以及对大剂量皮质类固醇以外的任何治疗无效。我们已经命名了 本病为VEXAS(空泡，E1酶，X连锁，自炎性躯体)综合征。患有疾病的患者 VEXAS综合征符合似乎完全不同的炎症(复发性多软骨炎， 结节性多动脉炎、巨细胞动脉炎)和血液病(骨髓增生异常综合征或浆细胞病) 条件。UBA1 p.Met41突变仅限于髓系，主要在淋巴系中缺失。 并导致严重的炎症性疾病。此外，我们还发现UBA1基因的突变位于 P.Met41导致蛋白异构体表达改变和有毒异构体的翻译。在这里提出的工作中， 我将研究髓系细胞中的马赛克突变如何导致髓系和淋巴系的异常发育。 以及细胞和分子水平的炎症(目标1)。然后我将描述流行率和 UBA1突变的外显性和其他迟发性炎症性诊断的其他遗传原因 (目标2)。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 严重的成人发病的炎症性疾病。我们对VEXAS综合征的研究结果表明，通过分析 在一系列严重炎症性疾病中，我们可以揭示共同的潜在遗传变异 发病机制，可能揭示临床上重要的疾病重新分类，并最终 从而改善临床护理。

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.