title: Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation.
abstract: We report a molecular study of the two known patients with autosomal recessive, partial interferon-γ receptor (IFN-γR)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-γR2 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-γ. 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-γ 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-γR2 protein. The diagnosis of partial IFN-γR2 deficiency is clinically useful, as affected patients should be treated with IFN-γ, [corrected] unlike patients with complete IFN-γR2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-γR2 deficiency due to misfolding or gain-of-glycosylation receptors.
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY;
authors: Marcela
authors: M
authors: Moncada-Vélez
authors: Rubén
authors: R
authors: Martinez-Barricarte
authors: Dusan
authors: D
authors: Bogunovic
authors: Xiao-Fei
authors: XF
authors: Kong
authors: Lizbeth
authors: L
authors: Blancas-Galicia
authors: Cengiz
authors: C
authors: Tirpan
authors: Guzide
authors: G
authors: Aksu
authors: Quentin B
authors: QB
authors: Vincent
authors: Bertrand
authors: B
authors: Boisson
authors: Yuval
authors: Y
authors: Itan
authors: Noé
authors: N
authors: Ramírez-Alejo
authors: Satoshi
authors: S
authors: Okada
authors: Alexandra Y
authors: AY
authors: Kreins
authors: Vanessa L
authors: VL
authors: Bryant
authors: Jose Luis
authors: JL
authors: Franco
authors: Mélanie
authors: M
authors: Migaud
authors: Sara
authors: S
authors: Espinosa-Padilla
authors: Marco
authors: M
authors: Yamazaki-Nakashimada
authors: Francisco
authors: F
authors: Espinosa-Rosales
authors: Necil
authors: N
authors: Kutukculer
authors: Laurent
authors: L
authors: Abel
authors: Jacinta
authors: J
authors: Bustamante
authors: Guillaume
authors: G
authors: Vogt
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Stéphanie
authors: S
authors: Boisson-Dupuis
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002648:Child; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D009164:Mycobacterium Infections / Q000235:genetics; D010375:Pedigree; D057165:Proteostasis Deficiencies / Q000235:genetics*; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics*; D014162:Transfection
chemical_list: D000470:Alkaloids; D004791:Enzyme Inhibitors; C086185:IFNGR2 protein, human; D017471:Receptors, Interferon; C065629:kifunensine
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