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Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette–Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)- γ  immunity. Germline bi-allelic mutations of  IFNGR2  can underlie partial or complete forms of IFN- γ  receptor 2 (IFN- γ R2) deficiency. Patients with partial IFN- γ R2 deficiency express a dysfunctional molecule on the cell surface. We studied three patients with MSMD from two unrelated kindreds from Turkey (P1, P2) and India (P3), by whole-exome sequencing. P1 and P2 are homozygous for a mutation of the initiation codon(c.1A&gt;G) of  IFNGR2 , whereas P3 is homozygous for a mutation of the second codon (c.4delC). Overexpressed mutant alleles produce small amounts of full-length IFN- γ R2 resulting in an impaired, but not abolished, response to IFN- γ . Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN- γ , and Epstein Barr virus-transformed B cells had a barely detectable response to IFN- γ . Studies in patients’ primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN- γ R2 protein of normal molecular weight and function is due to the initiation of translation between the second and ninth non-AUG codons. We thus describe mutations of the first and second codons of  IFNGR2 , which define a new form of partial recessive IFN- γ R2 deficiency. Residual levels of IFN- γ  signaling were very low, accounting for the more severe clinical phenotype of these patients  with residual expression levels of normally functional surface receptors than of patients with  partial recessive IFN- γ R2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN- γ  signaling were higher.

A purely quantitative form of partial recessive IFN- γ R2 deficiency caused by mutations of the initiation or second codon