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A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection

journal contribution
posted on 2023-06-08, 17:15 authored by Melanie NewportMelanie Newport, Clare M Huxley, Sara Huston, Catherine M Hawrylowicz, Ben A Oostra, Robert Williamson, Michael Levin
BACKGROUND Genetic differences in immune responses may affect susceptibility to mycobacterial infection, but no specific genes have been implicated in humans. We studied four children who had an unexplained genetic susceptibility to mycobacterial infection and who appeared to have inherited the same recessive mutation from a common ancestor. METHODS We used microsatellite analysis, immunofluorescence studies, and sequence analysis to study the affected patients, unaffected family members, and normal controls. RESULTS A genome search using microsatellite markers identified a region on chromosome 6q in which the affected children were all homozygous for eight markers. The gene for interferon-gamma receptor 1 maps to this region. Immunofluorescence studies showed that the receptor was absent on leukocytes from the affected children. Sequence analysis of complementary DNA for the gene for interferon-gamma receptor 1 revealed a point mutation at nucleotide 395 that introduces a stop codon and results in a truncated protein that lacks the transmembrane and cytoplasmic domains. CONCLUSIONS Four children with severe mycobacterial infections had a mutation in the gene for interferon-gamma receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor alpha by macrophages in response to interferon-gamma. The interferon-gamma pathway is important in the response to intracellular pathogens such as mycobacteria.

History

Publication status

  • Published

Journal

New England Journal of Medicine

ISSN

0028-4793

Publisher

Massachusetts Medical Society

Issue

26

Volume

335

Page range

1941-1949

Department affiliated with

  • Global Health and Infection Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2014-05-13

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