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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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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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
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