title: Deletion of the entire interferon-γ receptor 1 gene causing complete deficiency in three related patients.
abstract: OBJECTIVE
  Complete interferon-γ receptor 1 (IFN-γR1) deficiency is a primary immunodeficiency causing predisposition to severe infection due to intracellular pathogens. Only 36 cases have been reported worldwide. The purpose of this article is to describe a large novel deletion found in 3 related cases, which resulted in the complete removal of the IFNGR1 gene.
  
  
  METHODS
  Whole blood from three patients was stimulated with lipopolysaccharide (LPS) and IFN-γ to determine production of tumor necrosis factor (TNF), interleukin-12 p40 (IL-12p40) and IL-10. Expression of IFN-γR1 on the cell membrane of patients' monocytes was assessed using flow cytometry. IFNGR1 transcript was analyzed in RNA and the gene and adjacent regions were analyzed in DNA. Finally, IL22RA2 transcript levels were analyzed in whole blood cells and dendritic cells.
  
  
  RESULTS
  There was no expression of the IFN-γR1 on the monocytes. Consistent with this finding, there was no IFN-γ response in the whole blood assay as measured by effect on LPS-induced IL-12p40, TNF and IL-10 production. A 119.227 nt homozygous deletion on chromosome 6q23.3 was identified, removing the IFNGR1 gene completely and ending 117 nt upstream of the transcription start of the IL22RA2 gene. Transcript levels of IL22RA2 were similar in patient and control.
  
  
  CONCLUSIONS
  We identified the first large genomic deletion of IFNGR1 causing complete IFN-γR1 deficiency. Despite the deletion ending very close to the IL22RA2 gene, it does not appear to affect IL22RA2 transcription and, therefore, may not have any additional clinical consequence.
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Inge C
authors.initials: IC
authors.lastname: de Vor
authors.affiliation: Department of Pediatrics, Medical Center Haaglanden, Lijnbaan 32, 2512 VA, The Hague, The Netherlands.
authors.forename: Pomme M
authors.initials: PM
authors.lastname: van der Meulen
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bekker
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Els M
authors.initials: EM
authors.lastname: Verhard
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.affiliation: Department of Pediatrics, Medical Center Haaglanden, Lijnbaan 32, 2512 VA, The Hague, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Harnisch
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Maarten J D
authors.initials: MJ
authors.lastname: van Tol
authors.affiliation: Department of Pediatrics, Medical Center Haaglanden, Lijnbaan 32, 2512 VA, The Hague, The Netherlands.
authors.forename: Jantien W
authors.initials: JW
authors.lastname: Wieringa
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. r.g.m.bredius@lumc.nl.
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
mesh_terms: D000328:Adult; D001773:Blood Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D007223:Infant; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009894:Opportunistic Infections / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D010375:Pedigree; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics* / Q000276:immunology; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D016753:Interleukin-10; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C508609:IL10 protein, human; C433253:IL22RA2 protein, human
keywords: EBV; IFN-γR1 deficiency; IFNGR1; IL22RA2; MSMD; Mycobacterium fortuitum