Partial IFN-gamma R2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

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dc.contributor.authorMoncada-Velez, Marcela
dc.contributor.authorMartinez-Barricarte, Ruben
dc.contributor.authorBogunovic, Dusan
dc.contributor.authorKong, Xiao-Fei
dc.contributor.authorBlancas-Galicia, Lizbeth
dc.contributor.authorTirpan, Cengiz
dc.contributor.authorAksu, Guzide
dc.contributor.authorVincent, Quentin B.
dc.contributor.authorBoisson, Bertrand
dc.contributor.authorItan, Yuval
dc.contributor.authorRamirez-Alejo, Noe
dc.contributor.authorOkada, Satoshi
dc.contributor.authorKreins, Alexandra Y.
dc.contributor.authorBryant, Vanessa L.
dc.contributor.authorLuis Franco, Jose
dc.contributor.authorMigaud, Melanie
dc.contributor.authorEspinosa-Padilla, Sara
dc.contributor.authorYamazaki-Nakashimada, Marco
dc.contributor.authorEspinosa-Rosales, Francisco
dc.contributor.authorKutukculer, Necil
dc.contributor.authorAbel, Laurent
dc.contributor.authorBustamante, Jacinta
dc.contributor.authorVogt, Guillaume
dc.contributor.authorCasanova, Jean-Laurent
dc.contributor.authorBoisson-Dupuis, Stephanie
dc.date.accessioned2019-10-27T22:07:37Z
dc.date.available2019-10-27T22:07:37Z
dc.date.issued2013
dc.departmentEge Üniversitesien_US
dc.description.abstractWe 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.en_US
dc.description.sponsorshipEuropean Research CouncilEuropean Research Council (ERC) [ERC-2010-AdG-268777]; Institut National de la Sante et de la Recherche Medicale, University Paris Descartes, French National Agency for Research (ANR)French National Research Agency (ANR); EUEuropean Union (EU) [HEALTH-F3-2008-200732]; Bill and Melinda Gates FoundationGates 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 DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [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-Dapsensen_US
dc.description.sponsorshipThis work was supported by grants from the 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), the EU-grant HOMITB (grant HEALTH-F3-2008-200732), the Bill and Melinda Gates Foundation, the St. Giles Foundation, the Jeffrey Modell Foundation, and Talecris Biotherapeutics, Rockefeller University Center for Clinical and Translational Science grant 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the Rockefeller University, and the National Institute of Allergy and Infectious Diseases (grant 1R01AI089970). R.M.-B. is supported by the EMBO Long Term Fellowship program. X.-F.K. is supported by the Stony Wold-Herbert Fund, Choh-Hao Li Memorial Fund Scholar award, and the Shanghai Educational Development Foundation, Y.I. was supported by the AXA Research Fund. V.L.B. was supported by the Stony Wold-Herbert Fund, and A.Y.K. was supported by the Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapsens.en_US
dc.identifier.doi10.1182/blood-2013-01-480814en_US
dc.identifier.endpage2401en_US
dc.identifier.issn0006-4971
dc.identifier.issn1528-0020
dc.identifier.issue14en_US
dc.identifier.pmid23963039en_US
dc.identifier.startpage2390en_US
dc.identifier.urihttps://doi.org/10.1182/blood-2013-01-480814
dc.identifier.urihttps://hdl.handle.net/11454/49046
dc.identifier.volume122en_US
dc.identifier.wosWOS:000326078200022en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Soc Hematologyen_US
dc.relation.ispartofBlooden_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titlePartial IFN-gamma R2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylationen_US
dc.typeArticleen_US

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