A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection
| Autor: | Dinakantha S. Kumararatne, Stéphanie Dupuis, Salma Lamhamedi-Cherradi, Steven M. Holland, David Edgar, Vas Novelli, Alain Fischer, Jane R. Clarke, Klaus Heyne, Rainer Döffinger, Vivi-Anne Oxelius, Marie Claude Fondaneche, Melchiorre Brai, Jean-François Emile, Jean-Laurent Casanova, Frédéric Altare, John Girdlestone, David A. Lammas, Susan E. Dorman, Robert D. Schreiber, Henri Ducoulombier, Emmanuelle Jouanguy |
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| Rok vydání: | 1999 |
| Předmět: |
Adult
Male Heterozygote Adolescent Sequence analysis Mutant Gene Expression Virulence Immunogenetics Biology Transfection Mycobacterium Frameshift mutation Interferon-gamma Genetics Humans Genetic Predisposition to Disease RNA Messenger Allele Gene Receptors Interferon Sequence Deletion B-Lymphocytes Mycobacterium Infections Heterozygote advantage Fibroblasts Virology Pedigree DNA-Binding Proteins STAT1 Transcription Factor BCG Vaccine Trans-Activators Female |
| Zdroj: | Nature Genetics. 21:370-378 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/7701 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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