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Previous Volume 335:1941-1949 December 26, 1996 Number 26 Next

A Mutation in the Interferon- –Receptor Gene and Susceptibility to Mycobacterial Infection

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ABSTRACT

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- 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- 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- receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor by macrophages in response to interferon-. The interferon- pathway is important in the response to intracellular pathogens such as mycobacteria.

Source Information

From the Departments of Pediatrics (M.J.N., M.L.), Biochemistry and Molecular Genetics (M.J.N., C.M. Huxley, S.H., R.W.), and Immunology (C.M. Hawrylowicz), Imperial College School of Medicine at St. Mary's, London; and the Department of Clinical Genetics, Erasmus University, Rotterdam, the Netherlands (B.A.O.).

Address reprint requests to Dr. Levin at the Department of Pediatrics, Queen Elizabeth the Queen Mother Wing, St. Mary's Hospital, South Wharf Rd., London W2 1NY, United Kingdom.

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