A novel form of cell type-specific partial IFN-γR1 deficiency caused by a germ line mutation of the IFNGR1 initiation codon

IFN-gamma R1 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial diseases, and includes two forms of complete recessive deficiency, with or without cell surface expression, and two forms of partial deficiency, dominant or recessive. We report here a novel form of partial and recessive Interferon gamma receptor 1 (IFN-gamma R1) deficiency, which is almost as severe as complete deficiency. The patient is homozygous for a mutation of the initiation codon (M1K). No detectable expression and function of IFN-gamma R1 were found in the patient's fibroblasts. However, IFN-gamma R1 expression was found to be impaired, but not abolished, on the EBV-transformed B cells, which could respond weakly to IFN-gamma. The mechanism underlying this weak expression involves leaky translation initiation at both non-AUG codons and the third AUG codon at position 19. It results in the residual expression of IFN-gamma R1 protein of normal molecular weight and function. The residual IFN-gamma signaling documented in this novel form of partial IFN-gamma R1 deficiency was not ubiquitous and was milder than that seen in other forms of partial IFN-gamma R1 deficiency, accounting for the more severe clinical phenotype of the patient, which was almost as severe as that of patients with complete deficiency.