A purely quantitative form of partial recessive IFN-[gamma]R2 deficiency caused by mutations of the initiation or second codon.
Oleaga-Quintas, Carmen 1,2,3; Deswarte, Caroline 1,2; Moncada-Velez, Marcela 4,+ ; Metin, Ayse 5,+ ; Rao, Indumathi Krishna 6,+ ; Kan[latin dotless i]k-Yuksek, Saliha 5,+ ; Nieto-Patlan, Alejandro 1,2,+ ; Guerin, Antoine 1,2,+ ; Gulhan, Belgin 5,+ ; Murthy, Savita 6,+ ; Ozkaya-Parlakay, Asl[latin dotless i]nur 5,+ ; Abel, Laurent 1,2,7; Martinez-Barricarte, Ruben 7; de Diego, Rebeca Perez 8; Boisson-Dupuis, Stephanie 1,2,7,+ ; Kong, Xiao-Fei 7,+ ; Casanova, Jean-Laurent 1,2,7,9,10; Bustamante, Jacinta 1,2,7,11,*
[Article] Human Molecular Genetics. 27(22):3919-3935, November 2018.

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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-Guerin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-[gamma] immunity. Germline bi-allelic mutations of IFNGR2 can underlie partial or complete forms of IFN-[gamma] receptor 2 (IFN-[gamma]R2) deficiency. Patients with partial IFN-[gamma]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>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-[gamma]R2 resulting in an impaired, but not abolished, response to IFN-[gamma]. Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN-[gamma], and Epstein Barr virus-transformed B cells had a barely detectable response to IFN-[gamma]. Studies in patients' primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN-[gamma]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-[gamma]R2 deficiency. Residual levels of IFN-[gamma] 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-[gamma]R2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-[gamma] signaling were higher.

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