A point mutation in a domain of gamma interferon receptor 1 provokes severe immunodeficiency

Gamma interferon (IFN-gamma) and the cellular responses induced by it are e ssential for controlling mycobacterial infections, Most patients bearing an IFN-gamma receptor ligand-binding chain (IFN-gamma R1) deficiency present gross mutations that truncate the protein and prevent its expression, givin g rise to severe mycobacterial infections and, frequently, a fatal outcome. In this report a new mutation that affects the IFN-gamma R1 ligand-binding domain in a Spanish patient with mycobacterial disseminated infection and multifocal osteomyelitis is characterized, The mutation generates an amino acid change that does not abrogate protein expression on the cellular surfa ce but that severely impairs responses after the binding of IFN-gamma (CD64 and HLA class II induction and tumor necrosis factor alpha and interleukin -12 production), A patient's younger brother, who was also probably homozyg ous for the mutation, died from meningitis due to Mycobacterium bovis, Thes e findings suggest that a point mutation may be fatal when it affects funct ionally important domains of the receptor and that the severity is not dire ctly related to a lack of IFN-gamma receptor expression, Future research on these non-truncating mutations will make it possible to develop new therap eutical alternatives in this group of patients.