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 Abel & 5 others Capucine Picard, Damien J. Chaussabel, Jacinta Bustamante, Jean Laurent Casanova, Stéphanie Boisson-Dupuis

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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
Article numberdds484
Pages (from-to)769-781
Number of pages13
JournalHuman Molecular Genetics
Volume22
Issue number4
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

Fingerprint

Haploinsufficiency
Interferon-gamma
Exome
T-Lymphocytes
Frameshift Mutation
Penetrance
Myeloid Cells
Human Herpesvirus 4
Fathers
Interleukin-4
Monocytes
B-Lymphocytes
Alleles
Macrophages

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kong, X. F., Vogt, G., Itan, Y., Macura-Biegun, A., Szaflarska, A., Kowalczyk, D., ... Boisson-Dupuis, S. (2013). Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. Human Molecular Genetics, 22(4), 769-781. [dds484]. https://doi.org/10.1093/hmg/dds484

Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. / Kong, Xiao Fei; Vogt, Guillaume; Itan, Yuval; Macura-Biegun, Anna; Szaflarska, Anna; Kowalczyk, Danuta; Chapgier, Ariane; Abhyankar, Avinash; Furthner, Dieter; Djambas Khayat, Claudia; Okada, Satoshi; Bryant, Vanessa L.; Bogunovic, Dusan; Kreins, Alexandra; Moncada-Vélez, Marcela; Migaud, Mélanie; Al-Ajaji, Sulaiman; Al-Muhsen, Saleh; Holland, Steven M.; Abel, Laurent; Picard, Capucine; Chaussabel, Damien J.; Bustamante, Jacinta; Casanova, Jean Laurent; Boisson-Dupuis, Stéphanie.

In: Human Molecular Genetics, Vol. 22, No. 4, dds484, 02.2013, p. 769-781.

Research output: Contribution to journalArticle

Kong, XF, Vogt, G, Itan, Y, Macura-Biegun, A, Szaflarska, A, Kowalczyk, D, Chapgier, A, Abhyankar, A, Furthner, D, Djambas Khayat, C, Okada, S, Bryant, VL, Bogunovic, D, Kreins, A, Moncada-Vélez, M, Migaud, M, Al-Ajaji, S, Al-Muhsen, S, Holland, SM, Abel, L, Picard, C, Chaussabel, DJ, Bustamante, J, Casanova, JL & Boisson-Dupuis, S 2013, 'Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease', Human Molecular Genetics, vol. 22, no. 4, dds484, pp. 769-781. https://doi.org/10.1093/hmg/dds484
Kong XF, Vogt G, Itan Y, Macura-Biegun A, Szaflarska A, Kowalczyk D et al. Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. Human Molecular Genetics. 2013 Feb;22(4):769-781. dds484. https://doi.org/10.1093/hmg/dds484
Kong, Xiao Fei ; Vogt, Guillaume ; Itan, Yuval ; Macura-Biegun, Anna ; Szaflarska, Anna ; Kowalczyk, Danuta ; Chapgier, Ariane ; Abhyankar, Avinash ; Furthner, Dieter ; Djambas Khayat, Claudia ; Okada, Satoshi ; Bryant, Vanessa L. ; Bogunovic, Dusan ; Kreins, Alexandra ; Moncada-Vélez, Marcela ; Migaud, Mélanie ; Al-Ajaji, Sulaiman ; Al-Muhsen, Saleh ; Holland, Steven M. ; Abel, Laurent ; Picard, Capucine ; Chaussabel, Damien J. ; Bustamante, Jacinta ; Casanova, Jean Laurent ; Boisson-Dupuis, Stéphanie. / Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 4. pp. 769-781.
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abstract = "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.",
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AU - Kong, Xiao Fei

AU - Vogt, Guillaume

AU - Itan, Yuval

AU - Macura-Biegun, Anna

AU - Szaflarska, Anna

AU - Kowalczyk, Danuta

AU - Chapgier, Ariane

AU - Abhyankar, Avinash

AU - Furthner, Dieter

AU - Djambas Khayat, Claudia

AU - Okada, Satoshi

AU - Bryant, Vanessa L.

AU - Bogunovic, Dusan

AU - Kreins, Alexandra

AU - Moncada-Vélez, Marcela

AU - Migaud, Mélanie

AU - Al-Ajaji, Sulaiman

AU - Al-Muhsen, Saleh

AU - Holland, Steven M.

AU - Abel, Laurent

AU - Picard, Capucine

AU - Chaussabel, Damien J.

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