A novel mutation in IFN-γ receptor 2 with dominant negative activity: Biological consequences of homozygous and heterozygous states

Sergio D. Rosenzweig, Susan E. Dorman, Gulbu Uzel, Stephen Shaw, Amy Scurlock, Margaret R. Brown, Rebecca H. Buckley, Steven M. Holland

Research output: Contribution to journalArticle

Abstract

We identified two siblings homozygous for a single base pair deletion in the IFN-γR2 transmembrane domain (791delG) who presented with multifocal Mycobacterium abscessus osteomyelitis (patient 1) and disseminated CMV and Mycobacterium avium complex infection (patient 2), respectively. Although the patients showed no IFN-γR activity, their healthy heterozygous parents showed only partial IFN-γR activity. An HLA-identical bone marrow transplant from the mother led patient 1 to complete hemopoietic reconstitution, but only partial IFN-γR function. We cloned and expressed fluorescent fusion proteins of the wild-type IFN-γR2, an IFN-γR2 mutant previously described to produce a complete autosomal recessive deficiency (278del2), and of 791delG to determine whether the intermediate phenotype in the 791delG heterozygous state was caused by haploinsufficiency or a dominant negative effect. When cotransfected together with the wild-type vector into IFN-γR2-deficient fibroblasts, the fusion protein with 791delG inhibited IFN-γR function by 48.7 ± 5%, whereas fusion proteins with 278de12 had no inhibitory effect. Confocal microscopy of 791delG fusion proteins showed aberrant diffuse intracellular accumulation without plasma membrane localization. The fusion protein created by 791delG did not complete Golgi processing, and was neither expressed on the plasma membrane, nor shed extracellularly. The mutant construct 791delG exerts dominant negative effects on IFN-γ signaling without cell surface display, suggesting that it is acting on pathways other than those involved in cell surface recognition of ligand.

Original languageEnglish (US)
Pages (from-to)4000-4008
Number of pages9
JournalJournal of Immunology
Volume173
Issue number6
StatePublished - Sep 15 2004
Externally publishedYes

Fingerprint

Mutation
Proteins
Cell Membrane
Haploinsufficiency
Mycobacterium avium Complex
Osteomyelitis
Mycobacterium
Confocal Microscopy
Base Pairing
Siblings
Fibroblasts
Parents
Bone Marrow
Mothers
Ligands
Transplants
Phenotype
Infection

ASJC Scopus subject areas

  • Immunology

Cite this

Rosenzweig, S. D., Dorman, S. E., Uzel, G., Shaw, S., Scurlock, A., Brown, M. R., ... Holland, S. M. (2004). A novel mutation in IFN-γ receptor 2 with dominant negative activity: Biological consequences of homozygous and heterozygous states. Journal of Immunology, 173(6), 4000-4008.

A novel mutation in IFN-γ receptor 2 with dominant negative activity : Biological consequences of homozygous and heterozygous states. / Rosenzweig, Sergio D.; Dorman, Susan E.; Uzel, Gulbu; Shaw, Stephen; Scurlock, Amy; Brown, Margaret R.; Buckley, Rebecca H.; Holland, Steven M.

In: Journal of Immunology, Vol. 173, No. 6, 15.09.2004, p. 4000-4008.

Research output: Contribution to journalArticle

Rosenzweig, SD, Dorman, SE, Uzel, G, Shaw, S, Scurlock, A, Brown, MR, Buckley, RH & Holland, SM 2004, 'A novel mutation in IFN-γ receptor 2 with dominant negative activity: Biological consequences of homozygous and heterozygous states', Journal of Immunology, vol. 173, no. 6, pp. 4000-4008.
Rosenzweig SD, Dorman SE, Uzel G, Shaw S, Scurlock A, Brown MR et al. A novel mutation in IFN-γ receptor 2 with dominant negative activity: Biological consequences of homozygous and heterozygous states. Journal of Immunology. 2004 Sep 15;173(6):4000-4008.
Rosenzweig, Sergio D. ; Dorman, Susan E. ; Uzel, Gulbu ; Shaw, Stephen ; Scurlock, Amy ; Brown, Margaret R. ; Buckley, Rebecca H. ; Holland, Steven M. / A novel mutation in IFN-γ receptor 2 with dominant negative activity : Biological consequences of homozygous and heterozygous states. In: Journal of Immunology. 2004 ; Vol. 173, No. 6. pp. 4000-4008.
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