Genome-Wide Dissection of Mendelian Susceptibility to Mycobacterial Disease

孟德尔易感性分枝杆菌病（MSMD）是一种原发性免疫缺陷综合征 特征在于由弱毒力分枝杆菌引起的严重疾病，如BCG疫苗， 环境分枝杆菌，在其他健康的患者。MSMD患者也容易受到 结核病和沙门氏菌病，但其他感染是罕见的。在20世纪50年代首次在临床上描述， MSMD的发病机制一直不清楚，直到1996年，当它的第一个遗传病因被破译， 干扰素-γ受体1（IFN-γ RI）缺乏的儿童。过去18年来MSMD的遗传解剖 已经鉴定了9个致病基因，包括7个常染色体基因（IFNGR 1，IFNGR 2，STAT 1，IL 12 B，IL 12 RB 1，IRF 8， ISG 15）和2个X连锁（NEMO、CYBB）基因。这些基因座的高水平等位基因异质性导致了 18种不同疾病的定义MSMD在这些疾病患者中的发病机制涉及 受损的白细胞介素-12（IL-12）依赖性IFN-γ免疫。然而，在700名患者中， 在我们实验室进行的测试中携带任何这些基因缺陷。我们假设其他患者的MSMD导致 来自其他单基因先天性免疫缺陷，可能但不一定涉及IL- 1 2 -IF N-Y 电路.我们的目标是通过以下无假设的全基因组（GW） 方法，基于X连锁基因缺陷的X连锁定位， 常染色体基因和全外显子组测序（WES）的其他新的MSMD引起的缺陷。我们 这些发现清楚地说明了GW方法的力量，特别是WES。从一个基本的生物学 从这个角度来看，这项研究将为免疫机制提供相当多的新见解， 分枝杆菌阐明MSMD的分子遗传学基础也将有助于阐明MSMD的发病机制。 分枝杆菌病，使其有可能为患者和遗传 家庭咨询。这一新的信息将为使用IFN-γ或其他细胞因子治疗肿瘤铺平道路。 治疗分枝杆菌疾病，除了抗生素。最后，MSMD的遗传解剖将 为在其他方面健康的儿童中进行严重结核病的基因解剖铺平了道路。 相关性（参见说明）： 已知的孟德尔易感性分枝杆菌病（MSMD）的遗传病因， （IFN）-v介导的免疫。近一半的MSMD患者缺乏遗传病因。我们假设 这些患者中的MSMD也是由于先天性免疫缺陷引起的，我们的目的是使用 无假设GW方法

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-y receptor 1 (IFN-yRI) deficiency. Genetic dissection of MSMD over the last 18 years has identified 9 morbid genes, including 7 autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8, ISG15) and 2 X-linked (NEMO, CYBB) genes. The high level of allelic heterogeneity at these loci has led to the definition of 18 distinct disorders. The pathogenesis of MSMD in patients with these disorders involves impaired interleukin-12 (IL-12)-dependent IFN-y immunity. However, only about half of the 700 patients tested in our lab 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 I L - 1 2 - I F N - Y circuit. We aim to identify new MSMD-causing genes by following a hypothesis-free, genome-wide (GW) approaches, based on X-linked mapping for defects in X-linked genes, homozygosity mapping for defects in autosomal genes, and whole-exome sequencing (WES) for other novel MSMD-causing defects. Our discoveries neatly illustrate the power of GW approaches, particularly WES. 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-y 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. RELEVANCE (See instructions): The known genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD) impair interferon (IFN)-v-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.