Mycobacterium simiae infection in two unrelated patients with different forms of inherited IFN-γR2 deficiency - PubMed (original) (raw)

Case Reports

doi: 10.1007/s10875-014-0085-5. Epub 2014 Aug 19.

Orli Megged, Polina Stepensky, Pierre Casimir, Marcela Moncada-Velez, Diana Averbuch, Marc Victor Assous, Omar Abuzaitoun, Xiao-Fei Kong, Vincent Pedergnana, Caroline Deswarte, Mélanie Migaud, Stefan Rose-John, Yuval Itan, Bertrand Boisson, Aziz Belkadi, Francesca Conti, Laurent Abel, Guillaume Vogt, Stephanie Boisson-Dupuis, Jean-Laurent Casanova, Jacinta Bustamante

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Case Reports

Mycobacterium simiae infection in two unrelated patients with different forms of inherited IFN-γR2 deficiency

Rubén Martínez-Barricarte et al. J Clin Immunol. 2014 Nov.

Abstract

Interferon-γ receptor 2 (IFN-γR2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-γR2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-γR2 defect was autosomal recessive and complete. The second patient was a girl with multiple disseminated mycobacterial infections, including infection with M. simiae. She died at the age of 5 years, a short time after the transplantation of umbilical cord blood cells from an unrelated donor. Her IFN-γR2 defect was autosomal recessive and partial. Autosomal recessive IFN-γR2 deficiency is life-threatening, even in its partial form, and genetic diagnosis and familial counseling are therefore particularly important for this condition. These two cases are the first of IFN-γR2 deficiency associated with M. simiae infection to be described.

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Conflict of interest statement

Conflict of interest: The authors have no conflict of interest to declare.

Figures

Fig. 1

Fig. 1. Loss-of-function IFNGR2 alleles associated with MSMD

a) Schematic representation of the human IFNGR2 gene and corresponding protein with all previously described MSMD-associated mutations: in blue, mutations causing AR complete IFN-γR2 deficiency with detectable surface expression; in red, AR IFN-γR2 deficiency with no receptor expression; in purple, AR partial IFN-γR2 deficiency, and in green, AD IFN-γR2 deficiency. The different domains of the protein are indicated as L (leader peptide), EC (extracellular domain), TM (transmembrane domain) and IC (intracellular domain). Below this diagram, the consequences of the two mutations described here are shown: in the middle panel, a short IFN-γR2 caused by the creation of a premature stop codon (Y179X) and at the bottom, a longer predicted protein caused by the c.958insT variant. The extra portion of the protein due to the frame shift is indicated at dark gray at the end of the diagram. b) Familial segregation of the two mutations (Y179X and c.958insT) found in IFNGR2. The index case (P1 and P2) of each pedigree is indicated with solid symbols and an arrow. Each kindred is designated by a capital letter (A-B), and each generation by a Roman numeral (I-II). c) Electropherograms of a wild-type homozygous individual, a heterozygous carrier and a homozygous carrier are shown in this panel, in which the position of the mutant form is indicated with an arrow. d) Overexpression of the WT and mutant alleles of IFNGR2 in IFN-γR2-deficient SV40-fibroblasts, revealing a lack of expression of Y179X and the residual expression of 958insT. The results presented are from one experiment representative of the three independent experiments carried out. e) EMSA was carried out after IFN-γ stimulation of the same transfected cells as in D. A complete absence of DNA binding was observed for the nonsense mutation. The frameshift insertion showed a partial DNA binding, which was comparable to a previously reported partial deficient mutation. The results shown are representative of five independent experiments.

Fig. 2

Fig. 2. Plasma IFN-γ concentration

Plasma IFN-γ concentrations of the patients carrying the reported mutations. These concentrations are higher than those in healthy controls. The graph shows IFN-γ concentrations for the different forms of IFN-γR2 deficiency. The values obtained for these two patients (P1, P2) are similar to those reported for other patients with AR IFN-γR2 deficiency.

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