A purely quantitative form of partial recessive IFN-γR2 deficiency caused by mutations of the initiation or second codon

Carmen Oleaga-Quintas, Caroline Deswarte, Marcela Moncada-Vélez, Ayse Metin, Indumathi Krishna Rao, Saliha Kanık-Yüksek, Alejandro Nieto-Patlán, Antoine Guérin, Belgin Gülhan, Savita Murthy, Aslınur Özkaya-Parlakay, Laurent Abel, Rubén Martínez-Barricarte, Rebeca Pérez De Diego, Stéphanie Boisson-Dupuis, Xiao Fei Kong, Jean Laurent Casanova, Jacinta Bustamante

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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-γR2) deficiency. Patients with partial IFN-γR2 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-γR2 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-γR2 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-γR2 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-γR2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-γ signaling were higher.

Original languageEnglish (US)
Pages (from-to)3919-3935
Number of pages17
JournalHuman molecular genetics
Issue number22
StatePublished - Nov 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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