Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome
Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome
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DOI：
10.1111/cei.13365
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发表时间：
2019-12-01
影响因子：
4.6
通讯作者：
Mukai, T.
中科院分区：
文献类型：
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作者：
Tsuji, S.;Matsuzaki, H.;Mukai, T.
肿瘤坏死因子（TNF）受体相关周期性综合征（TRAPS）是一种由TNFRSF1A基因杂合突变引起的自身炎症性疾病。尽管已有超过150个TNFRSF1A突变被报道与trap表型相关，但只有少数，如p.Thr79Met （T79M）和半胱氨酸突变，已被功能分析。我们在一个家族中发现了两名trap患者，他们在TNFRSF1A中携带了一种新的p.Gly87Val （G87V）突变和p.Thr90Ile （T90I）突变。在这项研究中，我们研究了这种新型G87V突变的功能特征。使用突变的TNF受体1 （TNF- r1）过表达细胞的体外分析表明，这种突变改变了TNF- r1的表达和功能，类似于先前鉴定的致病性T79M突变。具体来说，G87V和T79M突变抑制了转染细胞中突变体TNF-R1的细胞表面表达，而T90I突变对其没有影响。此外，携带G87V和T90I突变的trap患者外周血单个核细胞（PBMCs）显示线粒体活性氧（ROS）增加。此外，我们还探讨了各种toll样受体（TLR）配体对炎症反应的影响，揭示了trap患者的pbmc对TLR-2和TLR-4配体的高反应，白细胞介素(IL)-8和粒细胞-巨噬细胞集落刺激因子（GM-CSF）可能参与了trap的发病机制。这些发现表明，新发现的G87V突变是trap的致病突变之一。我们基于独特的trap相关突变的发现为更清晰地理解炎症反应提供了新的见解，这将是开发新的trap治疗和预防方法的基本发现。
Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.