Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity.
Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity.
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亚形核因子-kappaB 必需调节剂突变数据库和重建系统可识别表型和免疫多样性。
DOI：
10.1016/j.jaci.2008.08.018
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发表时间：
2008-12
影响因子：
14.2
通讯作者：
Orange, Jordan S.
中科院分区：
文献类型：
--
作者：
Hanson, Eric P.;Monaco-Shawver, Linda;Solt, Laura A.;Madge, Lisa A.;Banerjee, Pinaki P.;May, Michael J.;Orange, Jordan S.
人类亚型NEMO突变导致不同的临床免疫表型，但了解其范围和机制联系免疫功能和基因型是不完整的。我们创建并分析了一个亚纯型NEMO突变数据库，以确定表型谱及其相关基因型，并试图建立一个标准化的NEMO重建系统，以获得机制的见解。对72例NEMO突变个体进行表型分析。在复溶系统中进一步研究了NEMO L153 R和C417 R。评价TNF-α或Toll样受体5信号的NF-κB活化、程序性细胞死亡和A20基因表达。共鉴定出32种不同的突变; 53%影响锌指结构域。81%合并外胚层发育不良，76%合并严重化脓性感染，39%合并分枝杆菌感染，19%合并严重病毒感染，21%合并炎性疾病。36%的患者平均死亡年龄为6.4岁。CD 40、IL-1、TNF-α、TLR和TCR信号分别在15/16（94%）、6/7（86%）、9/11（77%）、9/14（64%）和7/18（39%）中受损。亚型重构NEMO缺陷细胞表现出部分恢复NEMO功能。尽管L153 R和C417 R均能抑制TLR和TNF-α诱导的NF-κB活化，但L153 R还能增加TNF-α诱导的程序性细胞死亡，并降低A20表达。不同的NEMO亚型定义了特定的疾病和遗传特征。重构系统可以独立于个体的遗传背景来识别亚同态的属性。L153 R重组细胞中的凋亡易感性定义了该突变的特定表型，其可能导致与其临床相关的过度炎症。
Human hypomorphic NEMO mutations cause diverse clinical immunologic phenotypes, but understanding their scope and mechanistic links immune function and genotype is incomplete. We created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights. Phenotypes of 72 individuals with NEMO mutations were compiled. NEMO L153R and C417R were investigated further in a reconstitution system. TNF-α or Toll-like receptor 5 signals were evaluated for NF-κB activation, programmed cell death, and A20 gene expression. 32 different mutations were identified; 53% affect the zinc finger domain. 81% were associated with Ectodermal dysplasia, 76% with serious pyogenic infection, 39% with mycobacterial infection, 19% with serious viral infection, 21% with inflammatory diseases. 36% died at a mean age of 6.4 years. CD40, IL-1, TNF-α, TLR, and TCR signals were impaired in 15/16 (94%), 6/7 (86%), 9/11 (77%), 9/14 (64%), and 7/18 (39%), respectively. Hypomorphism-reconstituted NEMO-deficient cells demonstrated partial restoration of NEMO functions. Although both L153R and C417R impaired TLR and TNF-α induced NF-κB activation, L153R also increased TNF-α-induced programmed cell death with decreased A20 expression. Distinct NEMO hypomorphs define specific disease and genetic characteristics. A reconstitution system can identify attributes of hypomorphisms independent of an individual’s genetic background. Apoptosis susceptibility in L153R reconstituted cells defines a specific phenotype of this mutation that likely contributes to the excessive inflammation with which it is clinically associated.
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影响因子：
14.2
作者：
Orange, JS;Jain, A;Bonilla, FA
通讯作者：
Bonilla, FA
X连锁对分枝杆菌的敏感性是由NEMO中的突变损害CD40依赖性IL-12产生引起的。
影响因子：
15.3
作者：
Filipe-Santos, Orchidee;Bustamante, Jacinta;Haverkamp, Margje H;Vinolo, Emilie;Ku, Cheng-Lung;Puel, Anne;Frucht, David M;Christel, Karin;von Bernuth, Horst;Jouanguy, Emmanuelle;Feinberg, Jacqueline;Durandy, Anne;Senechal, Brigitte;Chapgier, Ariane;Vogt, Guillaume;de Beaucoudrey, Ludovic;Fieschi, Claire;Picard, Capucine;Garfa, Meriem;Chemli, Jalel;Bejaoui, Mohamed;Tsolia, Maria N;Kutukculer, Necil;Plebani, Alessandro;Notarangelo, Luigi;Bodemer, Christine;Geissmann, Frederic;Israel, Alain;Veron, Michel;Knackstedt, Maike;Barbouche, Ridha;Abel, Laurent;Magdorf, Klaus;Gendrel, Dominique;Agou, Fabrice;Holland, Steven M;Casanova, Jean-Laurent
通讯作者：
Casanova, Jean-Laurent
影响因子：
4.8
作者：
Agou, F;Traincard, F;Véron, M
通讯作者：
Véron, M
影响因子：
8
作者：
Dupuis-Girod, S;Corradini, N;Bodemer, C
通讯作者：
Bodemer, C
影响因子：
2
作者：
Orstavik, KH;Kristiansen, M;Steen-Johnsen, J
通讯作者：
Steen-Johnsen, J