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

摘要: We identified two siblings homozygous for a single base pair deletion in the IFN-gammaR2 transmembrane domain (791delG) who presented with multifocal Mycobacterium abscessus osteomyelitis (patient 1) and disseminated CMV avium complex infection 2), respectively. Although patients showed no IFN-gammaR activity, their healthy heterozygous parents only partial activity. An HLA-identical bone marrow transplant from mother led patient 1 to complete hemopoietic reconstitution, but function. cloned expressed fluorescent fusion proteins of wild-type IFN-gammaR2, an mutant previously described produce autosomal recessive deficiency (278del2), 791delG determine whether intermediate phenotype state was caused by haploinsufficiency or dominant negative effect. When cotransfected together vector into IFN-gammaR2-deficient fibroblasts, protein inhibited function 48.7 +/- 5%, whereas 278del2 had inhibitory Confocal microscopy aberrant diffuse intracellular accumulation without plasma membrane localization. The created did not Golgi processing, neither on membrane, nor shed extracellularly. construct exerts effects IFN-gamma signaling cell surface display, suggesting that it is acting pathways other than those involved recognition ligand.