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 types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adolescent
-
Adult
-
B-Lymphocytes / drug effects
-
B-Lymphocytes / metabolism
-
BCG Vaccine / adverse effects
-
BCG Vaccine / therapeutic use
-
DNA-Binding Proteins / metabolism
-
Female
-
Fibroblasts / drug effects
-
Fibroblasts / immunology
-
Gene Expression
-
Genetic Predisposition to Disease / genetics*
-
Genetic Predisposition to Disease / immunology
-
Heterozygote
-
Humans
-
Interferon gamma Receptor
-
Interferon-gamma / pharmacology
-
Male
-
Mycobacterium / pathogenicity
-
Mycobacterium Infections / genetics
-
Mycobacterium Infections / immunology*
-
Pedigree
-
RNA, Messenger / metabolism
-
Receptors, Interferon / genetics*
-
Receptors, Interferon / metabolism
-
STAT1 Transcription Factor
-
Sequence Deletion*
-
Trans-Activators / metabolism
-
Transfection
Substances
-
BCG Vaccine
-
DNA-Binding Proteins
-
RNA, Messenger
-
Receptors, Interferon
-
STAT1 Transcription Factor
-
STAT1 protein, human
-
Trans-Activators
-
Interferon-gamma