Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease

Xiao Fei Kong, Guillaume Vogt, Yuval Itan, Anna Macura-Biegun, Anna Szaflarska, Danuta Kowalczyk, Ariane Chapgier, Avinash Abhyankar, Dieter Furthner, Claudia Djambas Khayat, Satoshi Okada, Vanessa L. Bryant, Dusan Bogunovic, Alexandra Kreins, Marcela Moncada-Vélez, Mélanie Migaud, Sulaiman Al-Ajaji, Saleh Al-Muhsen, Steven M. Holland, Laurent AbelCapucine Picard, Damien Chaussabel, Jacinta Bustamante, Jean Laurent Casanova, Stéphanie Boisson-Dupuis

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-γ). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-γ, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-γR2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFN-γ-related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-γR2 deficiency respond poorly to IFN-γ, in some cases as poorly as the cells of P1. Naive CD4+ T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-γ, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-γR2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-γR2 deficiency, resulting from haploinsufficiency, at least in lymphoid cells. The clinical penetrance of AD IFN-γR2 deficiency is incomplete, possibly due, at least partly, to the variability of cellular responses to IFN-γ in these individuals.

Original languageEnglish (US)
Article numberdds484
Pages (from-to)769-781
Number of pages13
JournalHuman molecular genetics
Issue number4
StatePublished - Feb 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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