先天性一氧化氮合酶 2 缺陷导致成人致命性巨细胞病毒感染
Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.
机构信息
From St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University (S.B.D., D.H., N.H., S.B., F.R., B.B., R.F., E.J., J.B., L.A., S.B.-D., J.-L.C.), the Department of Microbiology and Immunology, Weill Cornell Medicine (R.B., C.N.), and Howard Hughes Medical Institute (J.-L.C.) - all in New York; the Pediatric Respiratory Diseases Research Center (D.M., S.A.M.), the Department of Clinical Immunology and Infectious Diseases (D.M., N. Mansouri), and the Clinical Tuberculosis and Epidemiology Research Center (D.M., M.M.), National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; the Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), Paris University, Imagine Institute (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), and the Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP) (J.B.), and the Pediatric Immunology-Hematology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, and the Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt (J.-F.E.) - all in France; the Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany (A.-L.N.); the Research Branch, Sidra Medicine (M.R., T.K., F.A.A., N. Marr), and the College of Health and Life Sciences, Hamad Bin Khalifa University (N. Marr), Doha, Qatar; and the Division of Pulmonary Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (N. Mansouri).
出版信息
N Engl J Med. 2020 Jan 30;382(5):437-445. doi: 10.1056/NEJMoa1910640.
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 () 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 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all 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.).
背景
巨细胞病毒（CMV）可导致多种遗传性或获得性 T 细胞免疫缺陷的儿童和成人发生严重疾病，这些人易发生多种感染。在其他健康人群中，CMV 也很少引起疾病。特发性 CMV 疾病的发病机制尚不清楚。缺乏编码一氧化氮合酶 2（）基因的近交系小鼠易感染相关的鼠 CMV。
方法
我们研究了一名来自伊朗的 51 岁健康男性，他在急性 CMV 感染后出现进行性 CMV 疾病，29 个月后导致其死亡。我们假设该患者可能存在一种新型的先天性免疫缺陷。因此，我们进行了全外显子组测序，并进行了候选突变等位基因的实验测试。
结果
我们发现编码截断 NOS2 蛋白的基因中存在纯合移码突变，该突变不能产生一氧化氮，这表明该患者存在常染色体隐性 NOS2 缺乏症。此外，我们在公共数据库中发现的所有纯合突变均编码有功能的蛋白，而其他等位基因频率大于 0.001 的所有突变也均编码有功能的蛋白。
结论
这些发现表明，在该患者感染 CMV 之前，遗传的 NOS2 缺乏症在临床上一直处于沉默状态。此外，NOS2 似乎对该患者其他病原体的控制具有冗余性。（由国家转化医学研究中心等资助）。
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