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: 8726900
• 负责人: Jean-Laurent Casanova
• 金额: $ 41.69万
• 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/8726900
• 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; 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; 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; public health relevance; 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）：慢性粘膜皮肤念珠菌病（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病（CMCD）是CMC的一种遗传形式，其发病机制长期以来一直不清楚。我们对常染色体隐性（AR） IL-17RA和常染色体显性（AD） IL-17F缺陷的鉴定为在AD - CMCD中鉴定STAT1的线圈结构域（CCD）的种系突变铺平了道路。我们进一步发现(i)这些突变是功能获得性（GOF），增强了STAT1依赖的细胞对细胞因子的反应，特别是IL-27和ifn； （ii） CMC是由IL-17 T细胞发育受损引起的。我们之前报道过其他感染（包括分枝杆菌和病毒性疾病）患者的STAT1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、免疫学和临床特征在很大程度上仍然未知。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GOF等位基因