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

Abstract

Gamma interferon (IFN-gamma) and the cellular responses induced by it are essential for controlling mycobacterial infections. Most patients bearing an IFN-gamma receptor ligand-binding chain (IFN-gammaR1) deficiency present gross mutations that truncate the protein and prevent its expression, giving rise to severe mycobacterial infections and, frequently, a fatal outcome. In this report a new mutation that affects the IFN-gammaR1 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 surface 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 homozygous for the mutation, died from meningitis due to Mycobacterium bovis. These findings suggest that a point mutation may be fatal when it affects functionally important domains of the receptor and that the severity is not directly related to a lack of IFN-gamma receptor expression. Future research on these nontruncating mutations will make it possible to develop new therapeutical alternatives in this group of patients.

FIG. 1

New mutation Val63Gly in the ligand-binding domain of IFN-γR1. (a) Sequence of the new mutation boundaries. Italics, amino acids implicated in the binding of IFN-γ to its receptor ; roman amino acids conserved in murine IFN-γR1 . (b) Pedigree and SSCP intrafamilial segregation of the Val63Gly mutation compared with a control.

FIG. 2

Cytofluorographic analysis of CD119 expression in the patient and family. Dotted lines, isotypic control fluorescence; solid lines, positive fluorescence. The graph shows expression in peripheral blood lymphocytes; similar results were obtained in peripheral monocytes and granulocytes (data not shown).

FIG. 3

Immune function parameters of the mutated IFN-γR1. (a) TNF-α production by monocytes stimulated with medium, LPS, and LPS plus rhIFN-γ; (b) induction of CD64 in monocytes after stimulation with IFN-γ. ▵, isotypic control fluorescence; ○, expression of CD64 after 24 h of stimulation with medium alone; □, expression of CD64 after 24 h of stimulation with 1,000 IU of rhIFN-γ/ml.

FIG. 3

Immune function parameters of the mutated IFN-γR1. (a) TNF-α production by monocytes stimulated with medium, LPS, and LPS plus rhIFN-γ; (b) induction of CD64 in monocytes after stimulation with IFN-γ. ▵, isotypic control fluorescence; ○, expression of CD64 after 24 h of stimulation with medium alone; □, expression of CD64 after 24 h of stimulation with 1,000 IU of rhIFN-γ/ml.