title: Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.
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.
authors.affiliation: St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Kong
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vogt
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.forename: Anna
authors.initials: A
authors.lastname: Macura-Biegun
authors.forename: Anna
authors.initials: A
authors.lastname: Szaflarska
authors.forename: Danuta
authors.initials: D
authors.lastname: Kowalczyk
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Dieter
authors.initials: D
authors.lastname: Furthner
authors.forename: Claudia
authors.initials: C
authors.lastname: Djambas Khayat
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Bryant
authors.forename: Dusan
authors.initials: D
authors.lastname: Bogunovic
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kreins
authors.forename: Marcela
authors.initials: M
authors.lastname: Moncada-Vélez
authors.forename: Mélanie
authors.initials: M
authors.lastname: Migaud
authors.forename: Sulaiman
authors.initials: S
authors.lastname: Al-Ajaji
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
mesh_terms: D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D009164:Mycobacterium Infections / Q000235:genetics; D009165:Mycobacterium Infections, Nontuberculous / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: C086185:IFNGR2 protein, human; D017471:Receptors, Interferon; D007371:Interferon-gamma