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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：
10331035
负责人：
Jacinta Bustamante
金额：
$ 50.85万
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 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10331035
关键词：
Affect Alleles Architecture Awareness BCG Vaccine Candidate Disease Gene Candidiasis Child Clinical Communicable Diseases Data Defect Development Disease Dissection Dominant Genetic Conditions Enrollment Etiology Exons Experimental Genetics Family Genes Genetic Genetic Counseling Genetic Diseases Genetic Heterogeneity Genetic Models Genetic Predisposition to Disease Genetic study Genotype Genus Mycobacterium Hematopoietic Stem Cell Transplantation Hereditary Disease Heterogeneity Human Human Genetics IFNGR1 gene IFNGR2 gene IL12B gene IL12RB1 gene IL12RB2 gene IRF1 gene ISG15 gene Immunity Immunologics Impairment Individual Interferon Type II Interferons International Introns Investigation JAK1 gene Laboratories Leadership Lesion Life Link Mediating Medical Molecular Molecular Diagnosis Molecular Genetics Mutate Mutation Parents Pathogenesis Pathway interactions Patient Recruitments Patients Penetrance Phenotype Physicians Physiological Predisposition Preventive Primary Infection Publications Recombinants Research Research Project Grants Role STAT1 gene Salmonella Savings Siblings Structure Syndrome TYK2 Technology Testing Therapeutic Therapeutic Uses Tuberculosis United States National Institutes of Health Ursidae Family Validation Variant Virulent Virus Diseases Work base candidate selection cohort computerized tools disease-causing mutation exome sequencing genome sequencing genome-wide innovation insight kindred macrophage microorganism mycobacterial novel pathogen protein expression receptor recessive genetic trait recurrent infection response trait whole genome

项目摘要

Project Summary Mendelian susceptibility to mycobacterial disease (MSMD) is a genetic and selective predisposition to clinical disease caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM). Patients with MSMD are occasionally vulnerable to other intra-macrophagic pathogens (e.g. salmonella). The pathogenesis of MSMD remained unclear until 1996, when its first genetic etiology was deciphered in children with interferon-γ receptor 1 (IFN-γR1) deficiency. Genetic studies over the last 25 years have identified 16 MSMD-causing genes, including 14 autosomal (IFNG, IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IL12RB2, IL23R, IRF8, SPPL2A, RORC, ISG15, TYK2, JAK1) and 2 X-linked genes (NEMO, CYBB). The high level of allelic heterogeneity at these loci has defined 31 distinct disorders. There is however physiological homogeneity, as all disorders impair IFN-γ immunity. Mutations in 5 genes (RORC, ISG15, TYK2, JAK1, STAT1) can underlie an atypical, syndromic form of MSMD, with an associated phenotype. With hindsight, MSMD is a misnomer, as most genetic etiologies show incomplete penetrance for MSMD. This serendipitously led to the discovery of genetic etiologies of bona fide tuberculosis. Remarkably, only about half of the 900 international patients studied in our lab carry MSMD-causing lesions in the exons and flanking intron regions at any of these 16 loci. In this renewal application, we hypothesize that unexplained MSMD cases can result from novel monogenic inborn errors of immunity, possibly but not necessarily involving IFN-γ mediated immunity. We aim to identify new MSMD-causing genes by following a genome-wide (GW) approach, based primarily but not exclusively on whole-exome sequencing (WES). We will enroll at least 50 MSMD patients each year. We will search for novel genetic etiologies by testing a hypothesis of genetic homogeneity, i.e. searching for genes mutated in two or more families. We will also test a hypothesis of genetic heterogeneity, i.e. searching for genes mutated in a single family. This search will benefit from our 12-year-long development of computational tools to analyze WES. Causal relationships between candidate genotypes and MSMD will be established experimentally in great mechanistic depth at the molecular, cellular, and immunological levels, taking advantage of cutting-edge technologies and our 25-year-long study of MSMD. In patients without candidate genotypes by WES, we will search for candidate regulatory variations in known and unknown MSMD-causing genes by whole genome sequencing (WGS). Our preliminary results are exciting, as we have identified MSMD-causing mutations in genes known to be crucial for IFN-γ immunity (TBX21, IRF1) and in other genes that probably disrupt IFN-γ immunity by novel mechanisms (ZNFX1, MCTS1). From an immunological standpoint, this research will provide novel insights into the mechanisms of human immunity to mycobacteria. From a medical standpoint, this work will provide molecular diagnoses for MSMD patients and genetic counseling for families, while offering the use of therapeutic IFN-γ, at least in patients whose genetic disorder does not abolish cellular responses to IFN-γ.

项目总结