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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

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Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation.

Moncada-Vélez Marcela M Martinez-Barricarte Rubén R Bogunovic Dusan D Kong Xiao-Fei XF Blancas-Galicia Lizbeth L Tirpan Cengiz C Aksu Guzide G Vincent Quentin B QB Boisson Bertrand B Itan Yuval Y Ramírez-Alejo Noé N Okada Satoshi S Kreins Alexandra Y AY Bryant Vanessa L VL Franco Jose Luis JL Migaud Mélanie M Espinosa-Padilla Sara S Yamazaki-Nakashimada Marco M Espinosa-Rosales Francisco F Kutukculer Necil N Abel Laurent L Bustamante Jacinta J Vogt Guillaume G Casanova Jean-Laurent JL Boisson-Dupuis Stéphanie S

Blood 20130820 14

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 ...[more]

PMID: 23963039

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Project description:Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.

Dataset Information

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

Publications

Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation.

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