Journal
HUMAN MOLECULAR GENETICS
Volume 22, Issue 4, Pages 769-781Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds484
Keywords
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Funding
- Stony Wold-Herbert Fund
- Choh-Hao Li Memorial Fund Scholar award
- Shanghai Educational Development Foundation
- AXA Research Fund
- Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapens
- St Giles Foundation
- Jeffrey Modell Foundation
- Rockefeller University Center for Clinical and Translational Science from the National Center for Research Resources [8UL1TR000043]
- National Center for Advancing Sciences (NCATS), National Institutes of Health
- National Institute of Allergy and Infectious Diseases [5R01AI089970-02]
- Rockefeller University
- European Research Council (ERC)
- Talecris BioTherapeutics
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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-). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-R2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFN--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-R2 deficiency respond poorly to IFN-, 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-, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-R2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-R2 deficiency, resulting from haploinsufficiency, at least in lymphoid cells. The clinical penetrance of AD IFN-R2 deficiency is incomplete, possibly due, at least partly, to the variability of cellular responses to IFN- in these individuals.
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