Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection
Open accessAbstract
IFN-gamma is critical in the immune response to mycobacterial infections, and deficits in IFN-gamma production and response have been associated with disseminated nontuberculous mycobacterial infections. Mutations in the IFN-gamma receptor ligand-binding chain (IFNgammaR1) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria. However, mutations in the IFN-gamma receptor signal-transducing chain (IFNgammaR2) have not been described. We describe a child with disseminated Mycobacterium fortuitum and M. avium complex infections and absent IFN-gamma signaling due to a mutation in the extracellular domain of IFNgammaR2. In vitro cytokine production by patient PBMCs showed 75% less PHA-induced IFN-gamma production than in normal cells, while patient PHA-induced TNF-alpha production was normal. The normal augmentation of TNF-alpha production when IFN-gamma was added to endotoxin was absent from patient cells. Expression of IFNgammaR1 was normal, but there was no phosphorylation of Stat1 in response to IFN-gamma stimulation. DNA sequence analysis of the gene for IFNgammaR2 showed a homozygous dinucleotide deletion at nucleotides 278 and 279, resulting in a premature stop codon in the protein extracellular domain. This novel gene defect associated with disseminated nontuberculous mycobacterial infection emphasizes the critical role that IFN-gamma plays in host defense against mycobacteria.
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Mutations in either subunit of the IFNGR result in increased risk of infections with mycobacteria.
“Notably, mutations in either subunit of the IFNGR result in increased risk of infections with mycobacteria (Dorman and Holland, 1998).”
From Iron in infection and immunity (2020) · cites this paper as Dorman and Holland, 1998
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- Authors
- Dorman, S. E., & Holland, S. M.
- Affiliations
- National Institutes of Health (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1998-06-01
- Volume
- 101
- Issue
- 11
- Pages
- 2364-2369
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508825
- OpenAlex
- W2076228603
- Cited by
- 429
- References
- 28
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 13 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 9 · 2016: 9 · 2015: 8 · 2014: 15 · 2013: 13 · 2012: 16
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Keywords
- IFNGR2, interferon-gamma signaling, nontuberculous mycobacterial infection, Mycobacterium fortuitum, Mycobacterium avium complex, disseminated mycobacterial infection, premature stop codon, STAT1 phosphorylation, TNF-alpha production, host defense against mycobacteria, genetic susceptibility
- MeSH terms
- Interferon gamma Receptor, Disease Susceptibility, Female, Humans, Infant, Newborn, Interferon-gamma, Male, Mutation, Mycobacterium Infections, Pregnancy, Signal Transduction, Receptors, Interferon
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