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Hum Mol Genet. 2018 Nov 15;27(22):3919-3935. doi: 10.1093/hmg/ddy275.

A purely quantitative form of partial recessive IFN-γR2 deficiency caused by mutations of the initiation or second codon.

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Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France.
Paris Descartes University, Paris, France.
Department of Immunology, School of Medicine, Complutense University, Madrid, Spain.
Primary Immunodeficiencies Group, School of Medicine, University of Antioquia UdeA, Medellin, Colombia.
Infectious Diseases Unit, Ankara Hematology Oncology Children's Training and Research Hospital, Ankara, Turkey.
Department of Pediatrics, St John's Medical College, Bangalore, India.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, the Rockefeller University, New York, USA.
Laboratory of Immunogenetics of Human Diseases IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain.
Howard Hughes Medical Institute, New York, USA.
Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.
Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.


Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi-allelic mutations of IFNGR2 can underlie partial or complete forms of IFN-γ receptor 2 (IFN-γR2) deficiency. Patients with partial IFN-γR2 deficiency express a dysfunctional molecule on the cell surface. We studied three patients with MSMD from two unrelated kindreds from Turkey (P1, P2) and India (P3), by whole-exome sequencing. P1 and P2 are homozygous for a mutation of the initiation codon(c.1A>G) of IFNGR2, whereas P3 is homozygous for a mutation of the second codon (c.4delC). Overexpressed mutant alleles produce small amounts of full-length IFN-γR2 resulting in an impaired, but not abolished, response to IFN-γ. Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN-γ, and Epstein Barr virus-transformed B cells had a barely detectable response to IFN-γ. Studies in patients' primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN-γR2 protein of normal molecular weight and function is due to the initiation of translation between the second and ninth non-AUG codons. We thus describe mutations of the first and second codons of IFNGR2, which define a new form of partial recessive IFN-γR2 deficiency. Residual levels of IFN-γ signaling were very low, accounting for the more severe clinical phenotype of these patients with residual expression levels of normally functional surface receptors than of patients with partial recessive IFN-γR2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-γ signaling were higher.

[Available on 2019-11-15]

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