A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Pedigrees of 12 families with mycobacterial infection.
Figure 2: Intrafamilial segregation of 818del4 and wild-type IFNGR1 alleles.
Figure 3: Cell-surface expression of IFNγR1 molecules in cells heterozygous for 818del4 and wild-type IFNGR1 alleles.
Figure 4: IFNγR1-mediated signalling in cells heterozygous for 818del4 and wild-type IFNGR1 alleles.
Figure 5: A hotspot for human small deletions.
Figure 6: Dominant-negative IFNγ receptors.

References

  1. 1

    WHO. Primary immunodeficiency diseases. Clin. Exp. Immunol. 109, 1–28 (1997).

  2. 2

    Abel, L. & Demenais, F. Detection of major genes for susceptibility to leprosy and its subtypes. Am. J. Hum. Genet. 42, 256–266 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Stead, W.W. Genetics and resistance to tuberculosis. Ann. Intern. Med. 116, 937–941 (1992).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Levin, M. et al. Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene? Lancet 345 , 79–83 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Casanova, J.L., Jouanguy, E., Lamhamedi, S., Blanche, S. & Fischer, A. Immunological conditions of children with BCG disseminated infection. Lancet 346, 581 (1995).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Casanova, J.L. et al. Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study. Pediatrics 98 , 774–778 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    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).

    CAS  PubMed  Google Scholar 

  8. 8

    McKusick, V.A. Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders (Johns Hopkins University Press, Baltimore, 1994).

    Google Scholar 

  9. 9

    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).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    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).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    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).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Roesler, J. et al. Recurrent mycobacterial and listeria infections in a child with interferon γ receptor deficiency. Exp. Haematol. (in press).

  16. 16

    Bach, E., Aguet, M. & Schreiber, R.D. The interferon γ receptor: a paradigm for cytokine receptor signaling. Annu. Rev. Immunol. 15, 563–591 (1997).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Jouanguy, E., Altare, F., Lamhamedi-Cherradi, S. & Casanova, J.L. Infections in IFNGR-1-deficient children. J. Interferon Cytokine Res. 17, 583–587 ( 1997).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    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).

    CAS  PubMed  Google Scholar 

  20. 20

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Altare, F. et al. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin infection. J. Clin. Invest. 102, 2035–2040 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Altare, F. et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280, 1432– 1435 (1998).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    de Jong, R. et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 280, 1435–1438 (1998).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Merlin, G. et al. The gene for the ligand-binding chain of the human IFNγ receptor. Immunogenetics 45, 413– 421 (1997).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Aguet, M., Dembic, Z. & Merlin, G. Molecular cloning and expression of the human IFNγ receptor. Cell 55, 273– 280 (1988).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Beaudet, A.L. & Tsui, L.C. A suggested nomenclature for designating mutations. Hum. Mut. 2, 245– 248 (1993).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    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).

    CAS  PubMed  Google Scholar 

  28. 28

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    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).

    CAS  Article  Google Scholar 

  30. 30

    Krawczak, M. & Cooper, D.N. Gene deletions. in Human Gene Mutations (eds Krawczak, M. & Cooper, D.N.) 163 –208 (Bios Scientific Publishers, Oxford, 1993).

    Google Scholar 

  31. 31

    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).

    Google Scholar 

  32. 32

    Efstratiadis, A. et al. The structure and evolution of the human β-globin gene family. Cell 21, 653–668 (1980).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Grundy, C.B. et al. Recurrent deletion in the human antithrombin III gene. Blood 78, 1027–1032 ( 1991).

    CAS  PubMed  Google Scholar 

  34. 34

    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).

    CAS  PubMed  Google Scholar 

  35. 35

    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).

    CAS  PubMed  Google Scholar 

  36. 36

    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).

    CAS  Article  Google Scholar 

  37. 37

    Dighe, A.S. et al. Tissue-specific targeting of cytokine unresponsiveness in transgenic mice. Immunity 3, 657– 666 (1995).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    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).

    Article  Google Scholar 

  39. 39

    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).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    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).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Altare, F. et al. Mendelian susceptibility to mycobacterial infections in man. Curr. Opin. Immunol. 10, 413– 417 (1998).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    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).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    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).

    CAS  Article  Google Scholar 

  44. 44

    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).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Heyne, K. Generalisatio BCG familiaris semibenigna, Osteomyelitis salmonellosa und Pseudotuberculosis intestinalis-Folgen eines familiären Makrophagendefektes. Eur. J. Pediatr. 121, 179–189 (1976).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Raszka, W.V., Trinh, T.T. & Zawadsky, P.M. Multifocal M. intracellular osteomyelitis in an immunocompetent child. Clin. Pediatr. 33, 611– 614 (1994).

    Article  Google Scholar 

  47. 47

    Bach, E. et al. Ligand-induced assembly and activation of the γ interferon receptor in intact cells. Mol. Cell. Biol. 16, 3214–3221 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    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).

    CAS  PubMed  Google Scholar 

  49. 49

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Bennett, R.L. et al. Recommendations for standardized human pedigree nomenclature. Am. J. Hum. Genet. 56, 745– 752 (1997).

    Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jean-Laurent Casanova.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jouanguy, E., Lamhamedi-Cherradi, S., Lammas, D. et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 21, 370–378 (1999). https://doi.org/10.1038/7701

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing