Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
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DOI：
10.1038/ng.2933
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发表时间：
2014-05
期刊：
影响因子：
30.8
通讯作者：
Crow YJ
中科院分区：
文献类型：
--
作者：
Rice GI;Del Toro Duany Y;Jenkinson EM;Forte GM;Anderson BH;Ariaudo G;Bader-Meunier B;Baildam EM;Battini R;Beresford MW;Casarano M;Chouchane M;Cimaz R;Collins AE;Cordeiro NJ;Dale RC;Davidson JE;De Waele L;Desguerre I;Faivre L;Fazzi E;Isidor B;Lagae L;Latchman AR;Lebon P;Li C;Livingston JH;Lourenço CM;Mancardi MM;Masurel-Paulet A;McInnes IB;Menezes MP;Mignot C;O'Sullivan J;Orcesi S;Picco PP;Riva E;Robinson RA;Rodriguez D;Salvatici E;Scott C;Szybowska M;Tolmie JL;Vanderver A;Vanhulle C;Vieira JP;Webb K;Whitney RN;Williams SG;Wolfe LA;Zuberi SM;Hur S;Crow YJ
I型干扰素系统是人类抗病毒免疫的组成部分。然而，不适当的刺激或该系统的负调节缺陷可导致炎性疾病。我们试图确定I型干扰素病Aicardi-Goutières综合征的遗传学未表征病例的分子基础，以及其他神经学和免疫学表型不明确的患者也表现出I型干扰素应答上调。我们发现，在胞质双链RNA受体基因IFIH 1（MDA 5）的杂合突变导致一系列的神经免疫学特征始终与增强的干扰素状态。细胞和生物化学分析表明，这些突变赋予了功能获得性-因此突变IFIH 1更积极地结合RNA，导致基线和配体诱导的干扰素信号传导增加。我们的研究结果表明，核酸的异常感应可以引起免疫上调。
The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, and of other patients with undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
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影响因子：
9.8
作者：
Rice, Gillian;Newman, William G.;Crow, Yanick J.
通讯作者：
Crow, Yanick J.
影响因子：
30.8
作者：
Briggs, Tracy A.;Rice, Gillian I.;Daly, Sarah;Urquhart, Jill;Gornall, Hannah;Bader-Meunier, Brigitte;Baskar, Kannan;Baskar, Shankar;Baudouin, Veronique;Beresford, Michael W.;Black, Graeme C. M.;Dearman, Rebecca J.;de Zegher, Francis;Foster, Emily S.;Frances, Camille;Hayman, Alison R.;Hilton, Emma;Job-Deslandre, Chantal;Kulkarni, Muralidhar L.;Le Merrer, Martine;Linglart, Agnes;Lovell, Simon C.;Maurer, Kathrin;Musset, Lucile;Navarro, Vincent;Picard, Capucine;Puel, Anne;Rieux-Laucat, Frederic;Roifman, Chaim M.;Scholl-Buergi, Sabine;Smith, Nigel;Szynkiewicz, Marcin;Wiedeman, Alice;Wouters, Carine;Zeef, Leo A. H.;Casanova, Jean-Laurent;Elkon, Keith B.;Janckila, Anthony;Lebon, Pierre;Crow, Yanick J.
通讯作者：
Crow, Yanick J.
一个 ADAR1 基因突变家族中的肌张力障碍、智力退化和对称性遗传色素沉着症
影响因子：
8.6
作者：
Tojo, Kana;Sekijima, Yoshiki;Ikeda, Shu-ichi
通讯作者：
Ikeda, Shu-ichi
DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
30.8
作者：
Crow, Yanick J.;Leitch, Andrea;Jackson, Andrew P.
通讯作者：
Jackson, Andrew P.