title: A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection.
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.
authors: INSERM U429, Hôpital Necker-Enfants Malades, Paris, France.
authors: E
authors: E
authors: Jouanguy
authors: S
authors: S
authors: Lamhamedi-Cherradi
authors: D
authors: D
authors: Lammas
authors: S E
authors: SE
authors: Dorman
authors: M C
authors: MC
authors: Fondanèche
authors: S
authors: S
authors: Dupuis
authors: R
authors: R
authors: Döffinger
authors: F
authors: F
authors: Altare
authors: J
authors: J
authors: Girdlestone
authors: J F
authors: JF
authors: Emile
authors: H
authors: H
authors: Ducoulombier
authors: D
authors: D
authors: Edgar
authors: J
authors: J
authors: Clarke
authors: V A
authors: VA
authors: Oxelius
authors: M
authors: M
authors: Brai
authors: V
authors: V
authors: Novelli
authors: K
authors: K
authors: Heyne
authors: A
authors: A
authors: Fischer
authors: S M
authors: SM
authors: Holland
authors: D S
authors: DS
authors: Kumararatne
authors: R D
authors: RD
authors: Schreiber
authors: J L
authors: JL
authors: Casanova
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001500:BCG Vaccine / Q000009:adverse effects / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics* / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D009161:Mycobacterium / Q000472:pathogenicity; D009164:Mycobacterium Infections / Q000235:genetics / Q000276:immunology*; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor; D017384:Sequence Deletion; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D000096743:Interferon gamma Receptor
chemical_list: D001500:BCG Vaccine; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human