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Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency
Scott B Drutman1, Davood Mansouri1, Seyed Alireza Mahdaviani1
1From 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).
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.).
Insights
A rare inherited nitric oxide synthase 2 (NOS2) deficiency was identified in a patient with severe Cytomegalovirus (CMV) disease. This genetic defect was previously unknown and clinically silent until CMV infection.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- Cytomegalovirus (CMV) can cause severe disease in immunocompromised individuals and rarely in healthy persons.
- The pathogenesis of idiopathic CMV disease remains unclear.
- Mice lacking nitric oxide synthase 2 (Nos2) are susceptible to murine CMV infection.
Observation:
- A previously healthy 51-year-old man developed progressive, fatal CMV disease following acute infection.
- Whole-exome sequencing was performed to investigate a potential novel inborn error of immunity.
Findings:
- A homozygous frameshift mutation in NOS2 was identified, confirming autosomal recessive NOS2 deficiency.
- The mutation resulted in a truncated NOS2 protein unable to produce nitric oxide.
- Other identified NOS2 variants in public databases encoded functional proteins.
Implications:
- Inherited NOS2 deficiency can be clinically silent until a severe opportunistic infection like CMV occurs.
- NOS2 may not be essential for controlling other pathogens in the absence of specific immune challenges.
- This study highlights a novel genetic basis for severe CMV disease in an otherwise healthy individual.
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