Partial IFN-?R2 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-? receptor (IFN-?R)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-?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-?. 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-? 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-?R2 protein. The diagnosis of partial IFN-?R2 deficiency is clinically useful, as affected patients should be treated with IFN-?, [corrected] unlike patients with complete IFN-?R2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-?R2 deficiency due to misfolding or gain-of-glycosylation receptors.

SUBMITTER: Moncada-Velez M 

PROVIDER: S-EPMC3790508 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature