Functional analysis of a new genetic variant suspected to cause a novel form of primary immunodeficiency featuring frequent respiratory infections, a susceptibility to herpesviral infection and lymphoid malignancy in three individuals.

对一种新的遗传变异进行功能分析，该变异被怀疑会导致三人出现一种新型原发性免疫缺陷，其特点是频繁呼吸道感染、对疱疹病毒感染和淋巴恶性肿瘤的易感性。

• 批准号: 389148238
• 负责人: Dr. Florian Gothe, Ph.D.
• 金额: --
• 依托单位: Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/389148238?language=en
• 关键词: Functional; analysis; new; genetic; variant

The main goal of this project is to test the hypothesis that inherited mutations in a particular gene can cause a novel form of primary immunodeficiency. DNA sequencing was carried out to discover the genetic change underlying a familial immunodeficiency that featured frequent respiratory infections, a susceptibility to herpesviral infection and lymphoid malignancy. The three affected individuals, in two generations of one family, share a novel genetic change affecting the amino acid sequence of a signaling adaptor protein. This protein is known to be important for specialized functions of immune cells including their ability to move towards sites of inflammation and to kill infected target cells.  However, there are no examples of human disease connected to this protein to date. We plan to study lymphoid cells of the patients functionally to unravel a suspected underlying inborn error of immunity and characterise it in molecular terms. This may suggest ways to diagnose and treat other patients with the same disorder.

该项目的主要目的是验证特定基因的遗传突变可导致一种新形式的原发性免疫缺陷的假设。进行DNA测序以发现家族性免疫缺陷的遗传变化，其特征是频繁的呼吸道感染，对疱疹病毒感染和淋巴系统恶性肿瘤的易感性。这三个受影响的个体，在一个家庭的两代人中，共享一种影响信号衔接蛋白氨基酸序列的新遗传变化。已知这种蛋白质对免疫细胞的特殊功能非常重要，包括它们向炎症部位移动和杀死受感染的靶细胞的能力。然而，迄今为止还没有与这种蛋白质有关的人类疾病的例子。我们计划从功能上研究患者的淋巴细胞，以解开一个可疑的潜在的先天性免疫缺陷，并从分子水平上证实它。这可能为诊断和治疗其他患有相同疾病的患者提供了方法。

项目成果

Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance

人白细胞介素 2 受体 β 突变与免疫和外周耐受缺陷相关

• DOI: 10.1084/jem.20182304
• 发表时间: 2019
• 期刊: The Journal of Experimental Medicine
• 作者: Zhang Z;Gothe F;Pennamen P;James JR;McDonald D;Mata CP;Modis Y;Alazami AM;Acres M;Haller W;Bowen C;Döffinger R;Sinclair J;Brothers S;Zhang Y;Matthews HF;Naudion S;Pelluard F;Alajlan H;Yamazaki Y;Notarangelo LD;Thaventhiran JE;Engelha
• 通讯作者: Engelha

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

• DOI: 10.1126/sciimmunol.aav7501
• 发表时间: 2019-12-01
• 期刊: SCIENCE IMMUNOLOGY
• 影响因子: 24.8
• 作者: Duncan, Christopher J. A.;Thompson, Benjamin J.;Briggs, Tracy A.
• 通讯作者: Briggs, Tracy A.