[HTML][HTML] A mutation in the interferon-γ–receptor gene and susceptibility to mycobacterial infection

MJ Newport, CM Huxley, S Huston… - … England Journal of …, 1996 - Mass Medical Soc
MJ Newport, CM Huxley, S Huston, CM Hawrylowicz, BA Oostra, R Williamson, M Levin
New England Journal of Medicine, 1996Mass Medical Soc
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 …
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-γ 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- γ 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-γ receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor α by macrophages in response to interferon-γ. The interferon-γ pathway is important in the response to intracellular pathogens such as mycobacteria.
The New England Journal Of Medicine