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Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.
The New England Journal of Medicine ( IF 70.670 ) Pub Date : 2020-01-30 , DOI: 10.1056/nejmoa1910640
Scott B Drutman,Davood Mansouri,Seyed Alireza Mahdaviani,Anna-Lena Neehus,David Hum,Ruslana Bryk,Nicholas Hernandez,Serkan Belkaya,Franck Rapaport,Benedetta Bigio,Robert Fisch,Mahbuba Rahman,Taushif Khan,Fatima Al Ali,Majid Marjani,Nahal Mansouri,Lazaro Lorenzo-Diaz,Jean-François Emile,Nico Marr,Emmanuelle Jouanguy,Jacinta Bustamante,Laurent Abel,Stéphanie Boisson-Dupuis,Vivien Béziat,Carl Nathan,Jean-Laurent Casanova

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.).
更新日期:2020-01-29

 

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