Genetics, Pathophysiology, and Treatment of Recessive Autoinflammatory Diseases

隐性自身炎症性疾病的遗传学、病理生理学和治疗

基本信息

批准号：
10499931
负责人：
Daniel Kastner
金额：
$ 222.17万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10499931
关键词：
ARID1A gene Age Animal Model Animals Arthritis Autoimmune Biochemical Biology Cell Death Cell Line Cells Chromatin Chronic Cleaved cell Clinical Clinical Research Collaborations Defect Development Diagnosis Disease Embryo Embryonic Development Enhancers Exhibits Fibroblasts Functional disorder Gene Expression Gene Frequency Genes Genetic Genomics Goals HTATIP2 gene Hematology Hepatitis B Virus Human In Vitro Individual Inflammatory Inherited Interferons Interleukin-6 Journals Lead Link Manuscripts Medicine Microscopic polyangiitis Minor Mutation NF-kappa B Names National Institute of Dental and Craniofacial Research New England Paper Pathogenicity Patients Phenotype Polyarteritis Nodosa Proteins Publishing RIPK1 gene Regulation Reporting Rheumatology Role Sampling Science Serum Signal Transduction Stroke prevention Syndrome System TBK1 gene TNF gene Testing Ubiquitin Variant Vasculitis Virus Diseases Wegener&apos s Granulomatosis adenosine deaminase deficiency autoinflammation autoinflammatory chromatin remodeling cohort congenital anomaly consanguineous family enzyme activity experience histone deacetylase 2 improved in vivo inhibitor/antagonist knockin animal knockout animal loss of function mutation peripheral blood prevent protein function response

项目摘要

During the current reporting period we focused on the following projects: 1) Deficiency of adenosine deaminase 2 (DADA2) In a previous reporting period, we published a manuscript in the New England Journal of Medicine demonstrating the efficacy of tumor necrosis factor (TNF) inhibitors in preventing strokes in DADA2. Our current cohort of DADA2 patients is now more than 55 patients, and we continue to observe that TNF inhibitors are highly effective in preventing strokes, although TNF inhibition does not appear to be effective in preventing the hematologic manifestations of DADA2. In collaboration with Peter Merkel and the Vasculitis Clinical Research Consortium, we have screened 117 patients with idiopathic polyarteritis nodosa (PAN), all of whom tested negative for hepatitis B virus infection, for ADA2 mutations. Four (3.4%) had biallelic rare missense variants in ADA2 with a minor allele frequency of less than 0.005. Of the 7 distinct variants present in these 4 patients, 6 had previously been reported as causative for DADA2, and the remaining variant is computationally predicted to be damaging to protein function. Four additional patients were carriers for monoallelic variants, one of which has been reported in DADA2 before. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA2 enzyme activity. ADA2 enzyme activity testing of 86 additional patients revealed 1 individual with strongly reduced ADA2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant at ADA2, with no other clinical differences noted. Of 1107 patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), none were homozygous or compound heterozygous for ADA2 mutations. A manuscript describing these findings was published in Arthritis and Rheumatology in March. 2) Description of LINKED, an X-linked recessive disorder presenting with multiple congenital anomalies and hemizygous mutations in OTUD5 Relying on genomic constraint scores, we identified 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. In collaboration with Achim Werner in NIDCR, we found that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. This study defined a previously unidentified disorder we named LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome that reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis. A paper describing these findings was published in Science Advances in January. 3) Autoinflammation due to TBK1 deficiency A collaborative study with Dusan Bogunovic identified four patients, ages 32, 26, 7, and 8 from 3 unrelated consanguineous families with homozygous loss-of-function mutations in TBK1, a regulator of IFN-I, NF-kB, and TNF-induced RIPK1-dependent cell death (RCD). All 4 patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We found that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-kB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD. A manuscript describing these findings was published in Cell in August.

报告期内，我们重点开展了以下项目： 1）腺苷脱氨酶2（DADA2）缺乏在上一个报告期，我们在《新英格兰医学杂志》上发表了一篇手稿，证明了肿瘤坏死因子 (TNF) 抑制剂在 DADA2 中预防中风的功效。我们目前的 DADA2 患者队列现已超过 55 名患者，我们继续观察到 TNF 抑制剂在预防中风方面非常有效，尽管 TNF 抑制似乎不能有效预防 DADA2 的血液学表现。我们与 Peter Merkel 和血管炎临床研究联盟合作，对 117 名特发性结节性多动脉炎 (PAN) 患者进行了筛查，所有患者的 ADA2 突变乙型肝炎病毒感染检测均为阴性。四人 (3.4%) 在 ADA2 中具有双等位基因罕见错义变异，次要等位基因频率小于 0.005。在这 4 名患者中存在的 7 种不同变异中，其中 6 种先前已被报道为 DADA2 的致病因素，而其余变异经计算预测会损害蛋白质功能。另外四名患者是单等位基因变异的携带者，其中之一之前已在 DADA2 中报道过。获得了 2 名具有双等位基因变异的 PAN 患者的血清样本，结果显示 ADA2 酶活性显着降低。对另外 86 名患者的 ADA2 酶活性检测显示，其中 1 名患者的 ADA2 活性严重降低，但未检测到致病变异。具有 PAN 和 ADA2 双等位基因变异的患者在诊断时比具有 1 个或无 ADA2 变异的患者更年轻，没有发现其他临床差异。在 1107 名肉芽肿性多血管炎 (GPA) 或显微镜下多血管炎 (MPA) 患者中，没有 ADA2 突变为纯合子或复合杂合子。描述这些发现的手稿于三月份发表在《关节炎和风湿病学》杂志上。 2) LINKED 的描述，一种 X 连锁隐性遗传病，表现为多种先天性异常和 OTUD5 半合子突变依靠基因组约束评分，我们鉴定了 10 名患有多种先天性异常的患者，这些先天异常是由编码 K48/K63 连锁特异性去泛素化酶的 OTUD5 半合子变异引起的。与 NIDCR 的 Achim Werner 合作，我们发现 OTUD5 通过裂解 K48 连接的泛素链来抵消选定染色质调节因子（例如 ARID1A/B、组蛋白脱乙酰酶 2 和 HCF1）的降解来控制神经外胚层分化，这些调节因子的突变是以下疾病的基础与 OTUD5 患者表现出表型重叠。分化过程中 OTUD5 的缺失会导致神经外胚层增强子处的染色质难以接近以及基因表达异常。这项研究定义了一种以前未识别的疾病，我们将其命名为LINKED（LINKage特异性去泛素化缺陷诱导的胚胎缺陷）综合征，该综合征揭示了染色质重塑剂的连锁特异性泛素裂解是胚胎发生过程中协调染色质重塑的重要信号传导模式。一篇描述这些发现的论文发表在一月份的《科学进展》上。 3) TBK1缺乏导致的自身炎症与 Dusan Bogunovic 的一项合作研究发现，来自 3 个不相关的近亲家庭的 4 名患者（年龄分别为 32、26、7 和 8 岁）患有 TBK1 纯合功能丧失突变，TBK1 是 IFN-I、NF-kB 和 TNF 诱导的调节因子RIPK1 依赖性细胞死亡 (RCD)。所有 4 名患者均患有慢性全身性自身炎症，但没有严重的病毒感染。我们发现TBK1缺失导致通过RIG-I/MDA5的低效但足够的IFN-I诱导，而系统通过NF-kB保留接近完整的IL-6诱导。自身炎症是由 TNF 诱导的 RCD 驱动的，因为患者来源的成纤维细胞在体外经历了更高的坏死性凋亡率，并且离体外周血中 CC3 升高。抗TNF治疗抑制了基线循环炎症状况并改善了体内临床状况。这些发现强调了 IFN-I 反应的可塑性，并强调了 TBK1 在 RCD 调节中的重要作用。描述这些发现的手稿于八月在《细胞》杂志上发表。