Deletion of the entire interferon-Î³ receptor 1 gene causing complete deficiency in three related patients.

de Vor, Inge C; van der Meulen, Pomme M; Bekker, Vincent; Verhard, Els M; Breuning, Martijn H; Harnisch, Esther; van Tol, Maarten J D; Wieringa, Jantien W; van de Vosse, Esther; Bredius, Robbert G M

de Vor, Inge C; van der Meulen, Pomme M; Bekker, Vincent; Verhard, Els M; Breuning, Martijn H; Harnisch, Esther; van Tol, Maarten J D; Wieringa, Jantien W; van de Vosse, Esther; Bredius, Robbert G M.

Afiliación

de Vor IC; Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
van der Meulen PM; Department of Pediatrics, Medical Center Haaglanden, Lijnbaan 32, 2512 VA, The Hague, The Netherlands.
Bekker V; Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Verhard EM; Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Breuning MH; Department of Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Harnisch E; Department of Pediatrics, Medical Center Haaglanden, Lijnbaan 32, 2512 VA, The Hague, The Netherlands.
van Tol MJ; Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Wieringa JW; Department of Pediatrics, Medical Center Haaglanden, Lijnbaan 32, 2512 VA, The Hague, The Netherlands.
van de Vosse E; Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Bredius RG; Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. r.g.m.bredius@lumc.nl.

J Clin Immunol ; 36(3): 195-203, 2016 Apr.

Article en En | MEDLINE | ID: mdl-26931784

RESUMEN

PURPOSE: Complete interferon-Î³ receptor 1 (IFN-Î³R1) 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-Î³ to determine production of tumor necrosis factor (TNF), interleukin-12 p40 (IL-12p40) and IL-10. Expression of IFN-Î³R1 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-Î³R1 on the monocytes. Consistent with this finding, there was no IFN-Î³ 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-Î³R1 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.

Asunto(s)

Eliminación de Gen; Síndromes de Inmunodeficiencia/genética; Infecciones Oportunistas/genética; ARN Mensajero/genética; Receptores de Interferón/genética; Receptores de Interleucina/genética; Adulto; Células Sanguíneas/efectos de los fármacos; Células Sanguíneas/inmunología; Células Sanguíneas/patología; Preescolar; Cromosomas Humanos Par 6; Células Dendríticas/inmunología; Células Dendríticas/patología; Femenino; Regulación de la Expresión Génica; Homocigoto; Humanos; Síndromes de Inmunodeficiencia/inmunología; Síndromes de Inmunodeficiencia/fisiopatología; Lactante; Interferón gamma/farmacología; Interleucina-10/genética; Interleucina-10/inmunología; Subunidad p40 de la Interleucina-12/genética; Subunidad p40 de la Interleucina-12/inmunología; Lipopolisacáridos/farmacología; Infecciones Oportunistas/inmunología; Infecciones Oportunistas/fisiopatología; Linaje; Cultivo Primario de Células; ARN Mensajero/inmunología; Receptores de Interferón/deficiencia; Receptores de Interferón/inmunología; Receptores de Interleucina/inmunología; Análisis de Secuencia de ADN; Transcripción Genética; Factor de Necrosis Tumoral alfa/genética; Factor de Necrosis Tumoral alfa/inmunología; Receptor de Interferón gamma

Palabras clave

EBV; IFN-Î³R1 deficiency; IFNGR1; IL22RA2; MSMD; Mycobacterium fortuitum

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones Oportunistas / ARN Mensajero / Receptores de Interferón / Eliminación de Gen / Receptores de Interleucina / Síndromes de Inmunodeficiencia Tipo de estudio: Prognostic_studies Idioma: En Revista: J Clin Immunol Año: 2016 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Países Bajos

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