Molecular, immunological, and clinical dissection of STAT1 hypermorphic mutations

STAT1 超态突变的分子、免疫学和临床剖析

• 批准号: 8898003
• 负责人: Jean-Laurent Casanova
• 金额: $ 40.99万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898003
• 关键词: Accounting; Address; Affect; Alleles; American; Antibodies; Autoimmune Diseases; Autoimmune Polyendocrinopathies; Autoimmunity; Biochemistry; Biological; CSF3 gene; Candida; Candidiasis; Cells; Cerebral Aneurysm; Chronic Mucocutaneous Candidiasis; Clinical; Coiled-Coil Domain; Communicable Diseases; Data; Dermatophytoses; Development; Diagnosis; Disease; Dissection; Dominant-Negative Mutation; Employee Strikes; Family; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genital system; Germ-Line Mutation; Health; Herpesviridae; Human; Human Genetics; Immune; Immunity; In Vitro; Inborn Genetic Diseases; Individual; Infection; Inherited; Interferons; Interleukin-17; International; Investigation; Job' s Syndrome; Malignant Neoplasms; Medical; Mendelian disorder; Missense Mutation; Molecular; Mucous Membrane; Mutation; Nail Diseases; Nail plate; Nuclear; Oral; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Physiological Processes; Production; Protein Dephosphorylation; Rare Diseases; Recurrence; Reporting; Research; STAT1 gene; STAT3 gene; Skin; Syndrome; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Thyroiditis; United States National Institutes of Health; Valproic Acid; Virus Diseases; base; clinical care; clinical phenotype; congenital immunodeficiency; cytokine; fungus; gain of function; gain of function mutation; in vivo; inhibitor/antagonist; innovation; insight; kindred; loss of function mutation; mycobacterial; novel; response; success; trait

DESCRIPTION (provided by applicant): Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent disease of the nails, skin, oral and genital mucosae. The pathogenesis of CMC disease (CMCD), a genetic form of CMC, has long remained elusive. Our identification of autosomal recessive (AR) IL-17RA and autosomal dominant (AD) IL-17F deficiencies paved the way for the identification of germ line mutations in the coiled-coil domain (CCD) of STAT1 in AD CMCD kindreds. We further showed that (i) the mutations were gain-of-function (GOF), enhancing STAT1- dependent cellular responses to cytokines, including IL-27 and IFNs in particular, and that (ii) CMC resulted from impaired development of IL-17 T cells. We had previously reported loss-of-function (LOF) mutations in STAT1 in patients with other infections, including mycobacterial and viral diseases. Astoundingly, STAT1 is the first human gene whose allelic diversity governs distinct infectious diseases. The molecular, immunological, and clinical features of patients with GOF STAT1 mutations however remain largely unknown. At the molecular level, we intend to describe the allelic diversity of GOF alleles and decipher the mechanism by which these various missense mutations of STAT1 are GOF. At the immunological level, we will test whether STAT1-dependent cytokines, such as IFNs and IL-27, impair the development of IL-17 T cells in vivo and in vitro, in both healthy controls and patients with GOF mutations. At the clinical level, we will thoroughly describe the clinical features of 25 American patients with CMCD sharing GOF STAT1 mutations, focusing in particular on phenotypes other than CMC, taking advantage of the capacity of the NIH Clinical Center. Overall, the molecular, immunological, and clinical features unraveled in this study will be integrated in order to define the causal relationships that determine the pathogenesis of CMC and other immunological and clinical phenotypes in patients with GOF STAT1 mutations. We have pioneered the human genetic dissection of inborn errors of both IL-17 and STAT1. We have already diagnosed 105 patients world-wide with GOF STAT1 mutations. We have shown that nearly a third of the mutations affect regions other than the CCD yet that all GOF mutations impair nuclear dephosphorylation of STAT1. We have also shown that IL-27 and IFNs inhibit the in vitro development of IL-17 T cells in patients with GOF STAT1 mutations, whereas antibodies against these cytokines rescue this phenotype. Finally, we have observed that many patients display features other than CMC, including auto-immunity, cerebral aneurysms, cancer, invasive fungal disease, and herpes virus reactivation. These preliminary data neatly illustrate the validit of our hypotheses, the power of our collaborative approach, and the potential of our integrated research. Our project is highly innovative, yet supported by strong preliminary evidence. This collaborative research will characterize the molecular, immunological, and clinical features of a unique human condition. The in-depth and integrated investigation of cells and patients with GOF STAT1 mutations has far- reaching and broad biological and clinical implications, for various physiological and pathological processes.

描述（由申请人提供）：慢性皮肤粘膜念珠菌病（CMC）的特征是指甲、皮肤、口腔和生殖器粘膜的复发性或持续性疾病。 CMC 疾病 (CMCD)（CMC 的一种遗传形式）的发病机制长期以来一直难以捉摸。我们对常染色体隐性 (AR) IL-17RA 和常染色体显性 (AD) IL-17F 缺陷的鉴定为鉴定 AD CMCD 亲属中 STAT1 卷曲螺旋结构域 (CCD) 种系突变铺平了道路。我们进一步表明（i）突变是功能获得（GOF），增强了STAT1依赖性细胞对细胞因子（尤其是IL-27和IFN）的反应，并且（ii）CMC是由IL-17 T细胞发育受损引起的。我们之前曾报道过患有其他感染（包括分枝杆菌和病毒性疾病）的患者中 STAT1 出现功能丧失（LOF）突变。令人惊讶的是，STAT1 是第一个等位基因多样性控制不同传染病的人类基因。然而，GOF STAT1 突变患者的分子、免疫学和临床特征仍然很大程度上未知。在分子水平上，我们打算描述 GOF 等位基因的等位基因多样性并破译 STAT1 的这些不同错义突变是 GOF 的机制。在免疫学水平上，我们将测试 STAT1 依赖性细胞因子（例如 IFN 和 IL-27）是否会在健康对照和患者体内和体外损害 IL-17 T 细胞的发育 与 GOF 突变。在临床层面，我们将利用 NIH 临床中心的能力，全面描述 25 名具有 GOF STAT1 突变的美国 CMCD 患者的临床特征，特别关注 CMC 以外的表型。总体而言，本研究中揭示的分子、免疫学和临床特征将被整合，以确定决定 GOF STAT1 突变患者 CMC 发病机制以及其他免疫学和临床表型的因果关系。我们率先对 IL-17 和 STAT1 的先天性缺陷进行了人类基因剖析。我们已经在全球诊断出 105 名患有 GOF STAT1 突变的患者。我们已经表明，近三分之一的突变影响 CCD 以外的区域，但所有 GOF 突变都会损害 STAT1 的核去磷酸化。我们还发现，IL-27 和 IFN 会抑制 GOF STAT1 突变患者体内 IL-17 T 细胞的体外发育，而针对这些细胞因子的抗体可以挽救这种表型。最后，我们观察到许多患者表现出 CMC 以外的特征，包括自身免疫、脑动脉瘤、癌症、侵袭性真菌病和疱疹病毒再激活。这些初步数据清楚地说明了我们假设的有效性、我们协作方法的力量以及我们综合研究的潜力。我们的项目具有高度创新性，但得到了强有力的初步证据的支持。这项合作研究将描述人类独特状况的分子、免疫学和临床特征。对 GOF STAT1 突变的细胞和患者进行深入和综合的研究对于各种生理和病理过程具有深远和广泛的生物学和临床意义。