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(Journal Article) |
Nature genetics 21 (4): 370-8 (1999)
A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection.
E Jouanguy
,
S Lamhamedi-Cherradi
,
D Lammas
,
S E Dorman
,
M C Fondanèche
,
S Dupuis
,
R Döffinger
,
F Altare
,
J Girdlestone
,
J F Emile
,
H Ducoulombier
,
D Edgar
,
J Clarke
,
V A Oxelius
,
M Brai
,
V Novelli
,
K Heyne
,
A Fischer
,
S M Holland
,
D S Kumararatne
,
R D Schreiber
,
J L Casanova
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.