Effect of amino acid substitutions in the human IFN-γR2 on IFN-γ responsiveness

Patients with interferon-gamma receptor (IFN-gamma R) null mutations have severe infections with poorly pathogenic Mycobacteria. The IFN-gamma R complex involves two IFN-gamma R1 and two IFN-gamma R2 chains, in which several amino acid substitutions, some linked to disease and some apparently naturally occurring, have been described. We developed a model system to study functional effects of genetic variations in IFN-gamma R2. We retrovirally transduced wild-type IFN-gamma R2 and IFN-gamma R2 carrying presently known amino acid substitutions in various human cell lines, and next determined the IFN-gamma R2 expression pattern as well as IFN-gamma responsiveness. We determined that the T58R, Q64R, E147K and K182E variants of IFN-gamma R2 are fully functional, although the Q64R variant may be expressed higher on the cell membrane. The R114C, T168N and G227R variants were identified in patients that had disseminated infections with non-tuberculous Mycobacteria. Of these genetic variants, T168N was confirmed to be completely non-functional, whereas the novel variant G227R, and the previously reported R114C, were partial functional. The impaired IFN-gamma responsiveness of R114C and G227R is mainly due to reduced receptor function, although expression on the cell membrane is reduced as well. We conclude that the T58R, Q64R, E147K and K182E variants are polymorphisms, whereas the R114C, T168N and G227R constitute mutations associated with disease. Genes and Immunity (2011) 12, 136-144; doi:10.1038/gene.2010.74; published online 20 January 2011