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

Emmanuelle Jouanguy, Salma Lamhamedi-Cherradi, David Lammas, Susan E. Dorman, Marie Claude Fondanèche, Stéphanie Dupuis, Rainer Döffinger, Frédéric Altare, John Girdlestone, Jean François Emile, Henri Ducoulombier, David Edgar, Jane Clarke, Vivi Anne Oxelius, Melchiorre Brai, Vas Novelli, Klaus Heyne, Alain Fischer, Steven M. Holland, Dinakantha S. KumararatneRobert D. Schreiber, Jean Laurent Casanova

Research output: Contribution to journalArticle

385 Scopus citations

Abstract

The immunogenetic basis of severe infections caused by bacille Calmette- Guerin 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.

Original languageEnglish
Pages (from-to)370-378
Number of pages9
JournalNature Genetics
Volume21
Issue number4
DOIs
StatePublished - Apr 1 1999

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    Jouanguy, E., Lamhamedi-Cherradi, S., Lammas, D., Dorman, S. E., Fondanèche, M. C., Dupuis, S., Döffinger, R., Altare, F., Girdlestone, J., Emile, J. F., Ducoulombier, H., Edgar, D., Clarke, J., Oxelius, V. A., Brai, M., Novelli, V., Heyne, K., Fischer, A., Holland, S. M., ... Casanova, J. L. (1999). A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nature Genetics, 21(4), 370-378. https://doi.org/10.1038/7701