TY - JOUR
T1 - Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation
AU - Moncada-Vélez, Marcela
AU - Martinez-Barricarte, Rubén
AU - Bogunovic, Dusan
AU - Kong, Xiao Fei
AU - Blancas-Galicia, Lizbeth
AU - Tirpan, Cengiz
AU - Aksu, Guzide
AU - Vincent, Quentin B.
AU - Boisson, Bertrand
AU - Itan, Yuval
AU - Ramírez-Alejo, Noé
AU - Okada, Satoshi
AU - Kreins, Alexandra Y.
AU - Bryant, Vanessa L.
AU - Franco, Jose Luis
AU - Migaud, Mélanie
AU - Espinosa-Padilla, Sara
AU - Yamazaki-Nakashimada, Marco
AU - Espinosa-Rosales, Francisco
AU - Kutukculer, Necil
AU - Abel, Laurent
AU - Bustamante, Jacinta
AU - Vogt, Guillaume
AU - Casanova, Jean Laurent
AU - Boisson-Dupuis, Stéphanie
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013
Y1 - 2013
N2 - 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-, 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.
AB - 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-, 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.
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U2 - 10.1182/blood-2013-01-480814
DO - 10.1182/blood-2013-01-480814
M3 - Article
C2 - 23963039
AN - SCOPUS:84887670038
SN - 0006-4971
VL - 122
SP - 2390
EP - 2401
JO - Blood
JF - Blood
IS - 14
ER -