TY - JOUR
T1 - Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease
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
AU - Bustamante, Jacinta
AU - Casanova, Jean Laurent
AU - Boisson-Dupuis, Stéphanie
N1 - Funding Information:
X.F.K. was supported by the Stony Wold-Herbert Fund, Choh-Hao Li Memorial Fund Scholar award and the Shanghai Educational Development Foundation, Y.I. is supported by the AXA Research Fund, V.L.B. is supported by the Stony Wold-Herbert Fund and A.K. is supported by the Fondation Médicale Medische Stichting Mathilde E. Horlait-Dapens. The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from the St Giles Foundation, the Jeffrey Modell Foundation, The Rockefeller University Center for Clinical and Translational Science grant number 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health, the National Institute of Allergy and Infectious Diseases grant number 5R01AI089970-02, The Rockefeller University and the European Research Council (ERC). J.L.C. received a research grant from the Jeffrey Modell Foundation in collaboration with Talecris BioTherapeutics. The funder was not involved in the study design; collection, analysis and interpretation of data; writing of the paper or decision to submit for publication.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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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U2 - 10.1093/hmg/dds484
DO - 10.1093/hmg/dds484
M3 - Article
C2 - 23161749
AN - SCOPUS:84873025890
SN - 0964-6906
VL - 22
SP - 769
EP - 781
JO - Human molecular genetics
JF - Human molecular genetics
IS - 4
M1 - dds484
ER -