期刊
BLOOD
卷 122, 期 14, 页码 2390-2401出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-01-480814
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资金
- European Research Council [ERC-2010-AdG-268777]
- Institut National de la Sante et de la Recherche Medicale, University Paris Descartes, French National Agency for Research (ANR)
- EU [HEALTH-F3-2008-200732]
- Bill and Melinda Gates Foundation
- St. Giles Foundation
- Jeffrey Modell Foundation
- Talecris Biotherapeutics
- Rockefeller University Center for Clinical and Translational Science from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) [8UL1TR000043]
- Rockefeller University
- National Institute of Allergy and Infectious Diseases [1R01AI089970]
- EMBO Long Term Fellowship program
- Stony Wold-Herbert Fund
- Choh-Hao Li Memorial Fund Scholar award
- Shanghai Educational Development Foundation
- AXA Research Fund
- Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapsens
- Grants-in-Aid for Scientific Research [25713039, 25670477] Funding Source: KAKEN
We report a molecular study of the two known patients with autosomal recessive, partial interferon-gamma receptor (IFN-gamma R)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-gamma R2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-gamma. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation. The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-gamma response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-gamma R2 protein. The diagnosis of partial IFN-gamma R2 deficiency is clinically useful, as affected patients should be treated with IFN-, unlike patients with complete IFN-gamma R2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-gamma R2 deficiency due to misfolding or gain-of-glycosylation receptors.
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