Mutation Analysis Of Selected Lymphoid Immune Disorders

特定淋巴免疫性疾病的突变分析

• 批准号: 8565338
• 负责人: thomas a fleisher
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8565338
• 关键词: Address; BIRC4 gene; Blood capillaries; CASP10 gene; CASP8 gene; CASP9 gene; DNA; DNA Resequencing; Data; Defect; Disease; Evaluation; Fluorescent Probes; Funding; Gene Chips; Genes; Genotype; Host Defense; IFNGR1 gene; IFNGR2 gene; IL12B gene; IL12RB1 gene; IL2RA gene; IL2RG gene; IRAK4 gene; Immune; Immune System Diseases; Immunoglobulin M; Immunologic Deficiency Syndromes; Infection; Interleukin 2 Receptor Gamma; Interleukin-12; Ions; JAK3 gene; KRAS2 gene; LIG4 gene; Lymphoid; Mutation; Mutation Analysis; NFKBIA gene; National Human Genome Research Institute; National Institute of Allergy and Infectious Disease; Organism; Patients; Phenotype; Process; Protocols documentation; Rag1 Mouse; Receptors, Adrenergic, beta-1; Recurrence; Research Personnel; STAT1 gene; STAT3 gene; STIM1 gene; Sampling; Screening procedure; Series; Speed; Syndrome; TLR3 gene; TNFRSF6 gene; TNFSF5 gene; United States National Institutes of Health; Work; alpha chain interleukin-7 receptor; artemis; autoimmune lymphoproliferative syndrome; capillary; clinical phenotype; congenital immunodeficiency; cost; human IFNGR1 protein; insight; interleukin-12 subunit p40; programs; web site

This project represents an extension of a long-standing series of collaborative studies performed to better characterize and understand immune deficiency. Mutations involving the genes for the common gamma chain (X-SCID) and Fas (ALPS) are being evaluated using direct gene sequencing with fluorescent probes. These studies have continued to identify a number of new mutations in both diseases and these data have been entered into the NIH NHGRI web site supporting each of these two disorders. This begane with an extensive evaluation of the gene encoding FAS (TNFRSF6) that confirmed 9 SNPs and identified two new SNPs among the control DNA samples evaluated. This was followed by the inclusion of mutation analysis of patients with hyper IgM syndrome directed at the genes encoding CD40L and NEMO with the latter focusing on a host of clinical phenotypes beyond the hyper IgM syndrome that has provided insight into genotype-phenotype variability. Additional sequencing for immune deficiency associated mutations has been added to deal with current protocols within NIAID focused on host defense defects with recurrent infections involving opportunisitc intracellular organisms including genes encoding the interferon gamma receptor 1 and 2, the IL-12P40 and IL-12 receptor beta 1 genes. A host of new mutations have been identified among all genes that are now being sequenced and over the past fiscal year a number of additional genes have been added to the repertoire including genes encoding: AIRE, ARTEMIS, BTK, FOXP3, ICOS, IL-7Ralpha, JAK3, mu heavy chain,SAP, WASp. The most recent additions to the mutation analysis menu represent a collaborative effort with investigators from the LHD and LCID in NIAID including the acquisition of an additional capillary sequencer supported by funds from the Scientific Director of NIAID. This program has expanded the number of genes evaluated associated with primary immunodeficiencies to 43: AID, CD40L, FAS, FASLG, KRAS, NRAS, IFNGR1, IFNGR2, IL12RB1, IL12B, IL2RG, NEMO, AIRE, BTK, CASP8, CASP9, CASP10, DKC1, ELA2, FOXP3, ICOS, IKBA, IRAK4, ITK, IL2RA, JAK3, LIG4, MYD88, NBN, NHEJ1, PRF1, RAG1, RAG2, STAT1, STAT3, STIM1, STX11, UNC13D, WAS, XIAP, SAP/SH2D1A, TLR3, ORAI1. In addition, we are now working on a NextGen approach to screening for specific immune defects focusing on disorders with common clinical phenotypes - this approach can prove to increase the speed with which a mutation is identified in a new patient as well as decrease the overall cost for this evaluation. Additional genetic defects associated with primary immunodeficiency disorders have been validated and are now included in the evaluation of CC patients with unknown immune disorders. In addition, the Next Gen resequencing platform, Ion Torrent, has been acquired and is in the process of validating a 150 gene chip to screen for primary immunodeficiencies.

该项目代表了一个长期的一系列合作研究的延伸，以更好地表征和了解免疫缺陷。涉及共同γ链（X-SCID）和Fas（ALPS）基因的突变正在使用荧光探针直接基因测序进行评估。这些研究继续在这两种疾病中鉴定出许多新的突变，这些数据已输入NIH NHGRI网站，支持这两种疾病中的每一种。 这开始于对编码FAS（TNFRSF 6）的基因的广泛评估，其确认了9个SNP，并在评估的对照DNA样品中鉴定了两个新的SNP。 随后纳入了针对编码CD 40 L和NEMO的基因的高IgM综合征患者的突变分析，后者重点关注高IgM综合征以外的许多临床表型，这提供了对基因型-表型变异性的深入了解。 已经增加了免疫缺陷相关突变的额外测序，以处理NIAID内的当前方案，该方案集中于涉及机会性细胞内生物体的复发性感染的宿主防御缺陷，包括编码干扰素γ受体1和2的基因、IL-12 P40和IL-12受体β 1基因。在目前正在测序的所有基因中已经鉴定出许多新的突变，并且在过去的财政年度中，许多额外的基因已经被添加到库中，包括编码以下的基因：AIRE、ARTEMIS、BTK、FOXP 3、ICOS、IL-7 Ra、JAK 3、mu重链、SAP、WASp。突变分析菜单的最新添加代表了与NIAID中LHD和LCID研究人员的合作努力，包括获得NIAID科学总监资助的额外毛细管测序仪。该计划将与原发性免疫缺陷相关的基因数量扩大到43个：AID、CD40L、FAS、FASLG、KRAS、NRAS、IFNGR1、IFNGR2、IL12RB1、IL12B、IL2RG、NEMO、AIRE、BTK、CASP8、CASP9、CASP10、DKC 1、ELA 2、FOXP 3、ICOS、IKBA、IRAK 4、ITK、IL2RA、JAK 3、LIG4、MYD 88、NBN、NHEJ1、PRF 1、RAG1、RAG2、STAT1、STAT3、STIM 1、STX11、UNC13D、WAS、XIAP、SAP/SH2D1A、TLR 3、ORAI 1。此外，我们现在正在研究一种NextGen方法来筛查特定的免疫缺陷，重点是具有常见临床表型的疾病-这种方法可以证明可以提高在新患者中识别突变的速度，并降低这种评估的总体成本。与原发性免疫缺陷疾病相关的其他遗传缺陷已经得到验证，现在被纳入对患有未知免疫疾病的CC患者的评估中。此外，已获得下一代重测序平台Ion Torrent，并正在验证150个基因芯片，以筛查原发性免疫缺陷。