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Publication Detail
Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Kong X-F, 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 D, Bustamante J, Casanova J-L, Boisson-Dupuis S
  • Publication date:
    15/02/2013
  • Pagination:
    769, 781
  • Journal:
    Hum Mol Genet
  • Volume:
    22
  • Issue:
    4
  • Status:
    Published
  • Country:
    England
  • PII:
    dds484
  • Language:
    eng
  • Keywords:
    Adolescent, B-Lymphocytes, Base Sequence, Case-Control Studies, Cells, Cultured, Female, Gene Expression, Genes, Dominant, Genetic Association Studies, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Humans, Interferon-gamma, Mycobacterium Infections, Mycobacterium Infections, Nontuberculous, Oligonucleotide Array Sequence Analysis, Pedigree, Phosphorylation, Protein Processing, Post-Translational, Receptors, Interferon, Sequence Analysis, DNA, Sequence Deletion
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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