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

作者：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^*

来源：Journal of Clinical Immunology, 2016, 36(3): 195-203.

DOI：10.1007/s10875-016-0244-y

• MSMD
• IFN-gamma R1 deficiency
• IFNGR1
• Mycobacterium fortuitum
• EBV
• IL22RA2

Complete interferon-gamma receptor 1 (IFN-gamma R1) 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.
Whole blood from three patients was stimulated with lipopolysaccharide (LPS) and IFN-gamma to determine production of tumor necrosis factor (TNF), interleukin-12 p40 (IL-12p40) and IL-10. Expression of IFN-gamma R1 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.
There was no expression of the IFN-gamma R1 on the monocytes. Consistent with this finding, there was no IFN-gamma 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.
We identified the first large genomic deletion of IFNGR1 causing complete IFN-gamma R1 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.

• 出版日期2016-4