TY - JOUR
T1 - A purely quantitative form of partial recessive IFN-γR2 deficiency caused by mutations of the initiation or second codon
AU - Oleaga-Quintas, Carmen
AU - Deswarte, Caroline
AU - Moncada-Vélez, Marcela
AU - Metin, Ayse
AU - Rao, Indumathi Krishna
AU - Kanık-Yüksek, Saliha
AU - Nieto-Patlán, Alejandro
AU - Guérin, Antoine
AU - Gülhan, Belgin
AU - Murthy, Savita
AU - Özkaya-Parlakay, Aslınur
AU - Abel, Laurent
AU - Martínez-Barricarte, Rubén
AU - De Diego, Rebeca Pérez
AU - Boisson-Dupuis, Stéphanie
AU - Kong, Xiao Fei
AU - Casanova, Jean Laurent
AU - Bustamante, Jacinta
N1 - Funding Information:
Paris Descartes University, the St. Giles Foundation and by the French National Research Agency (ANR) under the ‘Investments for the future’ program (ANR-10-IAHU-01); Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (ANR-10-LABX-62-IBEID) and GENMSMD grant (ANR-16-CE17-0005-01 to J.B.). SRC2017 to J.B. ANR-HGDIFD (ANR-14-CE15-006-01 by C.O.-Q. was supported by ANR-HGDIFD (ANR-14-CE15-006-01. A.G. was supported by ANR-IFNGPHOX (ANR13-ISV3-0001-01), ANR-GENMSMD (ANR-16-CE17-0005-01) and Imagine Institute.
Funding Information:
We would like to thank the patients and their families for their collaboration, and both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions and support. We would also like to thank Dominick Papandrea, Yelena Nemirovskaya, Cécile Patissier and Céline Desvallées for administrative support. We acknowledge use of the bioresources of the DNA biobank of the Imagine Institute (BB-033-00065). National Institute of Allergy and Infectious Diseases (5R37AI 095983); the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) of the National Institutes of Health (UL1TR001866); The Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, the St. Giles Foundation and by the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01); Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10LABX-62-IBEID) and GENMSMD grant (ANR-16-CE17-0005-01 to J.B.). SRC2017 to J.B. ANR-HGDIFD (ANR-14-CE15-006-01 by C.O.-Q. was supported by ANR-HGDIFD (ANR-14-CE15-006-01. A.G. was supported by ANR-IFNGPHOX (ANR13-ISV3-0001-01), ANR-GENMSMD (ANR-16-CE17-0005-01) and Imagine Institute.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddy275
DO - 10.1093/hmg/ddy275
M3 - Article
C2 - 31222290
AN - SCOPUS:85055698414
SN - 0964-6906
VL - 27
SP - 3919
EP - 3935
JO - Human molecular genetics
JF - Human molecular genetics
IS - 22
ER -