The immunogenetic basis of severe infections caused by bacille Calmette-Guérin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNγ receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNγ exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.
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WHO. Primary immunodeficiency diseases. Clin. Exp. Immunol. 109, 1–28 (1997).
Abel, L. & Demenais, F. Detection of major genes for susceptibility to leprosy and its subtypes. Am. J. Hum. Genet. 42, 256–266 (1988).
Stead, W.W. Genetics and resistance to tuberculosis. Ann. Intern. Med. 116, 937–941 (1992).
Levin, M. et al. Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene? Lancet 345 , 79–83 (1995).
Casanova, J.L., Jouanguy, E., Lamhamedi, S., Blanche, S. & Fischer, A. Immunological conditions of children with BCG disseminated infection. Lancet 346, 581 (1995).
Casanova, J.L. et al. Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study. Pediatrics 98 , 774–778 (1996).
Frucht, D.M. & Holland, S.M. Defective monocyte costimulation for IFN-γ production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation. J. Immunol. 157 , 411–416 (1996).
McKusick, V.A. Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders (Johns Hopkins University Press, Baltimore, 1994).
Emile, J.F. et al. Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection. J. Pathol. 181, 25–30 ( 1997).
Newport, M.J. et al. A mutation in the interferon-γ receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 335, 1941–1949 (1996).
Jouanguy, E. et al. Interferon-γ receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N. Engl. J. Med. 335, 1956–1961 (1996).
Pierre-Audigier, C. et al. Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon γ receptor deficiency. Clin. Infect. Dis. 24, 982–984 (1997).
Altare, F. et al. A causative relationship between mutant IFNγR1 alleles and impaired cellular response to IFNγ in a compound heterozygous child. Am. J. Hum. Genet. 62, 723– 726 (1998).
Holland, S.A. et al. Abnormal regulation of interferon γ, interleukin 12, and tumor necrosis factor γ in interferon γ receptor 1 deficiency. J. Infect. Dis. 178, 1095– 1104 (1998).
Roesler, J. et al. Recurrent mycobacterial and listeria infections in a child with interferon γ receptor deficiency. Exp. Haematol. (in press).
Bach, E., Aguet, M. & Schreiber, R.D. The interferon γ receptor: a paradigm for cytokine receptor signaling. Annu. Rev. Immunol. 15, 563–591 (1997).
Jouanguy, E. et al. Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J. Clin. Invest. 100, 2658 –2664 (1997).
Jouanguy, E., Altare, F., Lamhamedi-Cherradi, S. & Casanova, J.L. Infections in IFNGR-1-deficient children. J. Interferon Cytokine Res. 17, 583–587 ( 1997).
Lamhamedi, S., Jouanguy, E., Altare, F., Roesler, J. & Casanova, J.L. Interferon γ receptor deficiency: relationship between genotype, environment, and phenotype. Int. J. Mol. Med. 1, 415–418 ( 1998).
Dorman, S.E. & Holland, S.M. Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection. J. Clin. Invest. 101, 2364– 2369 (1998).
Altare, F. et al. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin infection. J. Clin. Invest. 102, 2035–2040 (1998).
Altare, F. et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280, 1432– 1435 (1998).
de Jong, R. et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 280, 1435–1438 (1998).
Merlin, G. et al. The gene for the ligand-binding chain of the human IFNγ receptor. Immunogenetics 45, 413– 421 (1997).
Aguet, M., Dembic, Z. & Merlin, G. Molecular cloning and expression of the human IFNγ receptor. Cell 55, 273– 280 (1988).
Beaudet, A.L. & Tsui, L.C. A suggested nomenclature for designating mutations. Hum. Mut. 2, 245– 248 (1993).
Farrar, M.A., Fernandez-Luna, J. & Schreiber, R.D. Identification of two regions within the cytoplasmic domain of the human IFNγ receptor required for function. J. Biol. Chem. 266, 19626–19635 (1991).
Greenlund, A.C., Farrar, M.A., Viviano, B.L. & Schreiber, R.D. Ligand-induced IFN γ receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 13 , 1591–1600 (1994).
Krawczak, M. & Cooper, D.N. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum. Genet. 86, 425– 441 (1991).
Krawczak, M. & Cooper, D.N. Gene deletions. in Human Gene Mutations (eds Krawczak, M. & Cooper, D.N.) 163 –208 (Bios Scientific Publishers, Oxford, 1993).
Cooper, D.N., Krawczak, M. & Antonarakis, S.E. The nature and mechanisms of human gene mutation. in The Genetic Basis of Cancer (eds Vogelstein, B. & Kinzler, K.W.) 65-95 (McGraw-Hill, New York, 1998).
Efstratiadis, A. et al. The structure and evolution of the human β-globin gene family. Cell 21, 653–668 (1980).
Grundy, C.B. et al. Recurrent deletion in the human antithrombin III gene. Blood 78, 1027–1032 ( 1991).
Weaver, D.T. & DePamphilis, M.L. Specific sequences in native DNA that arrest synthesis by DNA polymerase γ. J. Biol. Chem. 257, 2075–2086 ( 1982).
Dighe, A.S., Farrar, M.A. & Schreiber, R.D. Inhibition of cellular responsiveness to IFNγ induced by overexpression of inactive forms of the IFNγ receptor. J. Biol. Chem. 268, 10645–10653 (1993).
Dighe, A.S., Richards, E., Old, L.J. & Schreiber, R.D. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFNγ receptors. Immunity 1, 447–456 (1994).
Dighe, A.S. et al. Tissue-specific targeting of cytokine unresponsiveness in transgenic mice. Immunity 3, 657– 666 (1995).
Coughlin, C.M. et al. Tumor cell responses to IFNγ affect tumorigenicity and response to IL-12 therapy and angiogenesis. Immunity 9, 25–34 (1988).
Kaplan, D.H., Greenlund, A.C., Tanner, J.W., Shaw, S. & Schreiber, R.D. Identification of an IFNγ receptor γ chain sequence required for JAK-1 binding. J. Biol. Chem. 271, 9–12 ( 1996).
Farrar, M.A., Campbell, J.D. & Schreiber, R.D. Identification of a functionally important sequence motif in the carboxy terminus of the IFNγ receptor. Proc. Natl Acad. Sci. USA 89, 11706–11710 (1992).
Altare, F. et al. Mendelian susceptibility to mycobacterial infections in man. Curr. Opin. Immunol. 10, 413– 417 (1998).
Ottenhoff, T., Kumararatne, D. & Casanova, J.L. Novel immunodeficiencies reveal the essential role of type 1 cytokines in immunity to intracellular bacteria. Immunol. Today 19, 491–494 ( 1998).
Vidal, S., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73, 469–485 (1993).
Schonell, M.E., Crofton, J.W., Stuart, A.E. & Wallace, A. Disseminated infection with Mycobacterium avium: I. Clinical features, treatment and pathology. Tubercle 49, 12– 30 (1968).
Heyne, K. Generalisatio BCG familiaris semibenigna, Osteomyelitis salmonellosa und Pseudotuberculosis intestinalis-Folgen eines familiären Makrophagendefektes. Eur. J. Pediatr. 121, 179–189 (1976).
Raszka, W.V., Trinh, T.T. & Zawadsky, P.M. Multifocal M. intracellular osteomyelitis in an immunocompetent child. Clin. Pediatr. 33, 611– 614 (1994).
Bach, E. et al. Ligand-induced assembly and activation of the γ interferon receptor in intact cells. Mol. Cell. Biol. 16, 3214–3221 (1996).
Sheehan, K.C.F., Calderon, J. & Schreiber, R.D. Generation and characterization of monoclonal antibodies specific for the human IFNγ receptor. J. Immunol. 140, 4231–4237 (1988).
Celada, A., Allen, R., Esparza, I., Gray, P.W. & Schreiber, R.D. Demonstration and partial characterization of the interferon-γ receptor on human mononuclear phagocytes. J. Clin. Invest. 76, 2196–2205 (1985).
Bennett, R.L. et al. Recommendations for standardized human pedigree nomenclature. Am. J. Hum. Genet. 56, 745– 752 (1997).
We thank J. Peake for critical reading; C. Hivroz, F. Le Deist, B. Lisowska-Grospierre, M. Krawczak, C. Soudais and J. Wietzerbin for helpful discussions; D. Recan for EBV transformation of B cells; the late D. Lipscombe, who referred patients from kindred A for immunological assessment; and R.A. Thompson, who carried out the initial immunologic assessment. J.-L.C. thanks P. Even for encouragement and support. This work was supported by institutional grants from INSERM, AFM, PHRC, PNRFMMIP, MRC (UK) and West-Midland Regional Research Fund. E.J. is supported by the Ligue Nationale Contre le Cancer, S.L. by the Association Recherche et Partage, R.D. by the INSERM, F.A. by the AFM and D.L. by the Glaxo-Wellcome Action TB programme.
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