Inherited human IFN-γ deficiency underlies mycobacterial disease

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by BCG vaccines and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity, due to mutations of 15 genes controlling the production of, or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γR1 and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We report two Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del) causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss-of-expression and loss-of-function. We also show that the patients’ herpesvirus Saimiri-immortalized T lymphocytes do not produce IFN-γ, a phenotype that can be rescued by retrotransduction with wild-type IFNG cDNA. The blood T and NK lymphocytes of these patients also fail to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 and IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 and IFNGR2. This may account for the rarity of patients with autosomal recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.