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Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.
The New England Journal of Medicine ( IF 158.5 ) Pub Date : 2020-01-30 , DOI: 10.1056/nejmoa1910640
Scott B Drutman 1 , Davood Mansouri 1 , Seyed Alireza Mahdaviani 1 , Anna-Lena Neehus 1 , David Hum 1 , Ruslana Bryk 1 , Nicholas Hernandez 1 , Serkan Belkaya 1 , Franck Rapaport 1 , Benedetta Bigio 1 , Robert Fisch 1 , Mahbuba Rahman 1 , Taushif Khan 1 , Fatima Al Ali 1 , Majid Marjani 1 , Nahal Mansouri 1 , Lazaro Lorenzo-Diaz 1 , Jean-François Emile 1 , Nico Marr 1 , Emmanuelle Jouanguy 1 , Jacinta Bustamante 1 , Laurent Abel 1 , Stéphanie Boisson-Dupuis 1 , Vivien Béziat 1 , Carl Nathan 1 , Jean-Laurent Casanova 1
Affiliation  

BACKGROUND Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection. METHODS We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally. RESULTS We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001. CONCLUSIONS These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).

中文翻译:

患有遗传性NOS2缺乏症的成年人的致命性巨细胞病毒感染。

背景技术巨细胞病毒(CMV)可以在患有多种遗传或获得性T细胞免疫缺陷的儿童和成人中引起严重疾病,而这些疾病容易引起多重感染。它也很少会给其他健康人带来疾病。特发性CMV疾病的发病机制尚不清楚。缺少编码一氧化氮合酶2(Nos2)的基因的近交小鼠容易受到相关的鼠CMV感染。方法我们研究了来自伊朗的一名先前健康的51岁男性,该男性在急性CMV感染后开始进行性CMV疾病发作,导致其在29个月后死亡。我们假设患者可能患有新型的先天性免疫错误。因此,我们进行了全外显子测序并实验性地测试了候选突变等位基因。结果我们发现NOS2中的纯合移码突变编码不产生一氧化氮的截短的NOS2蛋白,这确定该患者患有常染色体隐性NOS2缺陷。此外,我们在公共数据库中的纯合性中发现的所有NOS2变体都编码功能蛋白,等位基因频率大于0.001的所有其他变体也是如此。结论这些发现表明,遗传性NOS2缺乏症在该患者中直到发生CMV致死性感染才在临床上保持沉默。此外,NOS2对于控制该患者的其他病原体似乎是多余的。(由国家转化科学促进中心等资助)。我们在公共数据库中的纯合性中发现的所有NOS2变体均编码功能蛋白,所有其他等位基因频率均大于0.001的变体也是如此。结论这些发现表明,遗传性NOS2缺乏症在该患者中直到发生CMV致死性感染才在临床上保持沉默。此外,NOS2对于控制该患者的其他病原体似乎是多余的。(由国家转化科学促进中心等资助)。我们在公共数据库中的纯合性中发现的所有NOS2变体均编码功能蛋白,所有其他等位基因频率均大于0.001的变体也是如此。结论这些发现表明,遗传性NOS2缺乏症在该患者中直到发生CMV致死性感染才在临床上保持沉默。此外,NOS2对于控制该患者的其他病原体似乎是多余的。(由国家转化科学促进中心等资助)。
更新日期:2020-01-29
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