Title | Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Drutman SB, Mansouri D, Mahdaviani SAlireza, Neehus A-L, Hum D, Bryk R, Hernandez N, Belkaya S, Rapaport F, Bigio B, Fisch R, Rahman M, Khan T, Ali FAl, Marjani M, Mansouri N, Lorenzo-Diaz L, Emile J-F, Marr N, Jouanguy E, Bustamante J, Abel L, Boisson-Dupuis S, Béziat V, Nathan C, Casanova J-L |
Journal | N Engl J Med |
Volume | 382 |
Issue | 5 |
Pagination | 437-445 |
Date Published | 2020 01 30 |
ISSN | 1533-4406 |
Keywords | Cytomegalovirus Infections, Fatal Outcome, Female, Frameshift Mutation, Genotype, Homozygote, Humans, Loss of Function Mutation, Male, Middle Aged, Nitric Oxide, Nitric Oxide Synthase Type II, Pedigree, Whole Exome Sequencing |
Abstract | 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.). |
DOI | 10.1056/NEJMoa1910640 |
Alternate Journal | N. Engl. J. Med. |
PubMed ID | 31995689 |
Grant List | UL1TR001866 / RR / NCRR NIH HHS / United States ANR-10-IAHU-01 / US / United States / United States ANR-10-LABX-62-IBEID / / Agence Nationale de la Recherche / International N/A / / St. Giles Foundation / International N/A / US / United States / United States Daland Fellowship / / American Philosophical Society / International ID NPRP9-251-3-045 / / Qatar National Research Fund / International |
Submitted by bel2021 on February 24, 2020 - 2:51pm