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

Hum Mol Genet. 2018 Nov 15;27(22):3919-3935. doi: 10.1093/hmg/ddy275.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Child
  • Child, Preschool
  • Codon, Initiator*
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Homozygote*
  • Humans
  • India
  • Infant
  • Infant, Newborn
  • Male
  • Mycobacterium Infections / genetics*
  • Receptors, Interferon / genetics*
  • Turkey
  • Whole Exome Sequencing


  • Codon, Initiator
  • IFNGR2 protein, human
  • Receptors, Interferon