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- Title
A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection.
- Authors
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; Kumararatne, D S; Schreiber, R D; Casanova, J L
- 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 IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma 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.
- Publication
Nature genetics, 1999, Vol 21, Issue 4, p370
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/7701