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

The immunogenetic basis of severe infections caused by bacille Calmette-Gue rin vaccine and environmental mycobacteria in humans remains largely unknow n. We describe 18 patients from several generations of 12 unrelated familie s who were heterozygous for 1 to 5 overlapping IFNCR1 frameshift small dele tions and a wild-type IFNGR1 allele. There were 12 independent mutation eve nts at a single mutation site, defining a small deletion hotspot. Neighbour ing sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFN gamma receptors that lack the intra-cytoplasmic domain, which, through a combina tion of impaired recycling, abrogated signalling and normal binding to IFN gamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections ca used by poorly virulent mycobacteria.