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

• 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
• 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' 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

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.

于本报告期内，我们专注于以下项目： 1)腺苷脱氨酶2（DADA 2）缺乏 在之前的报告期内，我们在新英格兰医学杂志上发表了一篇论文，证明了肿瘤坏死因子（TNF）抑制剂在预防DADA患者卒中中的疗效2。我们目前的DADA 2患者队列现在超过55例，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抑制剂似乎在预防DADA 2的血液学表现方面并不有效。 我们与Peter默克尔和血管炎临床研究联盟合作，筛选了117例原发性结节性多动脉炎（PAN）患者的ADA 2突变，所有患者的B型肝炎病毒感染检测均为阴性。4例（3.4%）患者在ADA 2中存在双等位基因罕见错义变体，次要等位基因频率小于0.005。在这4名患者中存在的7种不同变体中，6种先前已被报道为DADA 2的病因，并且计算预测剩余变体对蛋白质功能有损害。另外四名患者是单等位基因变体的携带者，其中一名之前已在DADA 2中报道过。可获得2例具有双等位基因变体的PAN患者的血清样品，其显示ADA 2酶活性显著降低。对另外86例患者进行的ADA 2酶活性检测显示，1例患者ADA 2活性显著降低，但未检出致病性变体。在ADA 2中具有PAN和双等位基因变体的患者在诊断时比在ADA 2中具有1个变体或没有变体的患者更年轻，没有观察到其他临床差异。在1107例肉芽肿伴多血管炎（GPA）或显微镜下多血管炎（MPA）患者中，没有一例是ADA 2突变的纯合子或复合杂合子。一份描述这些发现的手稿发表在三月份的《关节炎和风湿病学》上。 2)LINKED的描述，一种X连锁隐性疾病，表现为多个先天性异常和OTUD中的半合子突变5 依靠基因组约束评分，我们确定了10名患有由OTUD 5中编码K48/K63连接特异性去遍在酶的半合子变体引起的多种先天性异常的患者。与NIDCR的Achim Werner合作，我们发现OTUD 5通过切割K48连接的泛素链来控制神经外胚层分化，以抵消选择的染色质调节因子的降解（例如，ARID 1A/B、组蛋白脱乙酰酶2和HCF 1），其突变是表现出与OTUD 5患者表型重叠的疾病的基础。分化过程中OTUD 5的缺失导致神经外胚层增强子处的染色质不易接近和基因表达异常。这项研究定义了一种以前未识别的疾病，我们命名为LINKED（LINKage-specific deubiquitylation deficiency-induced Embryonic Defects）综合征，揭示了连接特异性泛素切割染色质重塑作为一种重要的信号传导模式，在胚胎发生过程中协调染色质重塑。一篇描述这些发现的论文发表在1月份的《科学进展》上。 3)TBK 1缺乏引起的自身炎症 与Dusan Bogunovic的一项合作研究确定了来自3个不相关的近亲家庭的4名患者，年龄分别为32岁，26岁，7岁和8岁，他们在TBK 1中具有纯合功能丧失突变，TBK 1是IFN-I，NF-kB和TNF诱导的RIPK 1依赖性细胞死亡（RCD）的调节因子。所有4名患者都患有慢性和全身性自身炎症，但没有严重的病毒感染。我们发现TBK 1的缺失导致通过RIG-I/MDA 5的亚纯型但足够的IFN-I诱导，而该系统通过NF-kB保持接近完整的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CC 3在离体外周血中升高。抗TNF治疗抑制了基线循环炎症特征并改善了体内临床状况。这些发现强调了IFN-I应答的可塑性，并强调了TBK 1在RCD调节中的重要作用。 描述这些发现的手稿于8月发表在Cell上。