Genome-wide dissection of Mendelian susceptibility to mycobacterial disease

孟德尔对分枝杆菌疾病易感性的全基因组解析

基本信息

批准号：
8162130
负责人：
Jean-Laurent Casanova
金额：
$ 42.25万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8162130
关键词：
Accounting Affect Antibiotics BCG Vaccine Biological Candidate Disease Gene Child Childhood Clinical Communicable Diseases Defect Development Disease Dissection Dominant Genetic Conditions Employee Strikes Family Family member Funding Genes Genetic Genetic Counseling Genetic Heterogeneity Genetic Predisposition to Disease Genus Mycobacterium Grant Hematopoietic Stem Cell Transplantation Hereditary Disease Herpes encephalitis Heterogeneity Host Defense Human IFNGR1 gene IFNGR2 gene IL12B gene IL12RB1 gene IL12RB2 gene Immunity Immunologic Deficiency Syndromes Inborn Genetic Diseases Individual Infection Interferon Receptor Interferons Interleukin-12 Investigation JAK2 gene Laboratories Life Light Link Maps Mediating Methods Minority Molecular Diagnosis Molecular Genetics Mutation Pathogenesis Pathway interactions Patients Physicians Pneumococcal Infections Predisposition Recombinant Interferon Recombinants Recurrence Research Role STAT1 gene Salmonella infections Syndrome TYK2 Testing Tuberculosis Ubiquitin United States National Institutes of Health Ursidae Family Variant Viral Virulent Work autosomal recessive trait base cytokine disease-causing mutation exome genome wide association study genome-wide genome-wide linkage innovation insight microorganism mycobacterial novel protein expression recessive genetic trait trait

项目摘要

DESCRIPTION (provided by applicant): Mendelian susceptibility to mycobacterial disease (MSMD) is a primary immunodeficiency syndrome characterized by severe disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy patients. Patients with MSMD are also vulnerable to tuberculosis and salmonellosis, though other infections are rare. First described clinically in the 1950s, the pathogenesis of MSMD remained unclear until 1996, when its first genetic etiology was deciphered in children with interferon- receptor 1 (IFN-R1) deficiency. Genetic dissection of MSMD over the last fifteen years has identified six morbid genes, including five autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1) and one X- linked (NEMO) gene. The high level of allelic heterogeneity at these six loci has led to the definition of up to 13 distinct disorders. The pathogenesis of MSMD in patients with these disorders involves impaired interleukin-12 (IL-12)-dependent IFN- immunity. However, only about half of the 600 patients tested in our laboratory carried any of these genetic defects. We hypothesize that MSMD in other patients results from other monogenic inborn errors of immunity, possibly but not necessarily involving the IL-12-IFN- circuit. A hypothesis-based, candidate gene approach focused on genes involved in the IL-12-IFN- circuit and related to the known MSMD-causing genes is being funded by the NIH grant 1R01AI089970. Therefore, the principal objective of the work described in this application is to identify new MSMD-causing genes by following a complementary, hypothesis-generating, genome-wide (GW) screening approach. In the present, GW approach, we will search for and characterize MSMD-causing genes by GW linkage (for both X-linked and autosomal recessive traits) and GW deep sequencing (by whole-exome sequencing). A novel method of GW linkage has been developed in the lab and whole-exome deep sequencing has been pioneered by our lab for other infectious diseases. Following this approach, we have obtained strong preliminary evidence of five novel MSMD-causing genes, with recessive mutations in X-linked CYBB and autosomal TYK2, JAK2, ISG15, and AP4E1. These five discoveries are very surprising, each in a unique way, and together they neatly illustrate the power of GW approaches and whole-exome sequencing in particular. Our project is therefore highly innovative, feasible, and supported by strong preliminary evidence. From a basic biological standpoint, this research will provide considerable and novel insights into the mechanisms of immunity to mycobacteria. Elucidation of the molecular genetic basis of MSMD will also shed light on the pathogenesis of mycobacterial disease, making it possible to provide molecular diagnoses for patients and genetic counseling for families. This new information will pave the way for the use of IFN- or other cytokines for the treatment of mycobacterial diseases, in addition to antibiotics. Finally, the genetic dissection of MSMD will pave the way for the genetic dissection of severe tuberculosis in otherwise healthy children. PUBLIC HEALTH RELEVANCE: The known genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD) impair interferon (IFN)--mediated immunity. Nearly half the patients with MSMD lack a genetic etiology. We hypothesize that MSMD in these patients also results from inborn errors of immunity, which we aim to identify using hypothesis- free, GW approaches.

描述（由申请人提供）：孟德尔对分枝杆菌疾病（MSMD）的易感性是一种原发性免疫缺陷综合症，其特征是由弱毒性分枝杆菌引起的严重疾病，例如BCG疫苗和环境分枝杆菌，在其他健康的患者中。 MSMD患者也很容易受到结核病和沙门氏菌病的影响，尽管其他感染很少。在1950年代，MSMD的发病机理首先在临床上进行描述，直到1996年，其第一个遗传病因在干扰素受体1（IFN-R1）缺陷的儿童中被解密。在过去的十五年中，MSMD的遗传解剖已经确定了六个病态基因，包括五个常染色体（IFNGR1，IFNGR2，STAT1，IL12B，IL12RB1）和一个X-链接（NeMO）基因。这六个基因座的等位基因异质性的高水平导致了多达13种不同疾病的定义。这些疾病患者中MSMD的发病机理涉及白介素12（IL-12）依赖性IFN-免疫性受损。但是，在我们实验室中测试的600名患者中，只有一半携带这些遗传缺陷。我们假设其他患者的MSMD是由于其他单基因先天性误差而导致的，可能但不一定涉及IL-12-IFN-回路。一种基于假设的候选基因方法，该方法重点介绍了IL-12-IFN-回路涉及的基因，并且与已知的MSMD引起基因有关，这是由NIH Grant 1R01AI089970资助的。因此，本应用中描述的工作的主要目标是通过遵循互补的，假设生成的，全基因组（GW）筛查方法来识别新的引起MSMD的基因。在目前的GW方法中，我们将通过GW链接（用于X连锁和常染色体隐性性状）和GW深度测序（通过全符号测序）来搜索并表征MSMD引起的基因。实验室已经开发了一种新型的GW连锁方法，我们的实验室为其他传染病率先提出了全面的深层测序。遵循这种方法，我们获得了五个新型引起MSMD的基因的强烈初步证据，X连锁CYBB和常染色体TYK2，JAK2，ISG15和AP4E1中有隐性突变。这五个发现非常令人惊讶，每种发现都以独特的方式，它们整洁地说明了GW方法的力量，尤其是整个外观测序的力量。因此，我们的项目具有很高的创新性，可行性，并且得到了强有力的初步证据的支持。从基本的生物学角度来看，这项研究将为对分枝杆菌的免疫机制提供大量新颖的见解。阐明MSMD的分子遗传基础还将阐明分枝杆菌疾病的发病机理，从而为患者提供分子诊断和家庭的遗传咨询。除抗生素外，这些新信息还将为使用IFN或其他细胞因子治疗分枝杆菌疾病铺平道路。最后，MSMD的遗传解剖会为其他健康儿童的严重结核病的遗传解剖铺平道路。公共卫生相关性：孟德尔对分枝杆菌疾病（MSMD）易感性的已知遗传病因损害了干扰素（IFN） - 介导的免疫力。 MSMD患者几乎一半缺乏遗传病因。我们假设这些患者中的MSMD也是由于先天免疫力而引起的，我们旨在使用无假设的GW方法来识别。