In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ

Jouanguy, Emmanuelle; Dupuis, Stéphanie; Pallier, Annaïck; Döffinger, Rainer; Fondanèche, Marie-Claude; Fieschi, Claire; Lamhamedi-Cherradi, Salma; Altare, Frédéric; Émile, Jean-François; Lutz, Patrick; Bordigoni, Pierre; Çokuğraş, Haluk; Akçakaya, Necla; Landman‐Parker, Judith; Donnadieu, J; Camcioğlu, Yıldız; Casanova, Jean‐Laurent

doi:10.1172/jci9166

Cited by 150 publications

(103 citation statements)

References 40 publications

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“…Relatively frequently, the syndrome of high susceptibility to unusual mycobacterial infections has been associated with causative, deleterious genetic mutations in the IFNGR1 gene (16)(17)(18). Therefore, we screened our two patients suffering from unusual mycobacterial infections for the expression of IFN-γ R1 proteins (CD119), using two different MAb's.…”

Section: Flow Cytometric Analysis Of Ifn-γ R1 Expressionmentioning

confidence: 99%

“…Mutations in the IFNGR1 gene can cause either complete or partial signaling defects, resulting in two distinct phenotypes (16)(17)(18). First, patients suffering from a complete signaling defect generally present with diffuse and poorly differentiated, lepromatoid-like granulomas with many bacilli, have a poor prognosis, and can only be treated by bone marrow transplantation (BMT).…”

Section: Introductionmentioning

confidence: 99%

“…Complete signaling defects can be divided into two subgroups, distinguishable by the absence or the presence of IFN-γ R1 protein expression on the surface membrane (SmIFN-γ R1). In cases with complete signaling defects but with the presence of SmIFN-γ R1, the causative defect is in the IFN-γ binding capacity of the IFN-γ R (18). Both subgroups show an autosomal recessive (AR) inheritance.…”

Section: Introductionmentioning

confidence: 99%

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Two Patients with Complete Defects in Interferon Gamma Receptor-Dependent Signaling

et al. 2007

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Unusual susceptibility to mycobacterial infections can be caused by deleterious mutations in genes that encode the interferon-γ receptor 1 chain. Such mutations hamper the activation of macrophages by a type 1 immune response and result in enhanced survival of intracellular pathogens. We here report two patients with unusual mycobacterial infections, both diagnosed with homozygous deleterious interferon-γ receptor 1 gene mutations. Patient 1 became ill after Bacillus CalmetteGuérin vaccination at the age of 9 months and died at the age of 18 months. She carried a homozygous C71Y mutation in the extracellular part of the mature interferon-γ receptor 1 protein, resulting in the lack of detectable protein expression and absence of interferon-γ dependent signaling. Patient 2 became ill at the age of 3 years, is still alive at 19 years of age, and has suffered from five successive infection episodes with atypical mycobacteria. A homozygous splice-site mutation in intron 3 was identified, resulting in the deletion of exon 3 at the mRNA level and consequently a truncated interferon-γ receptor 1 protein with absence of the transmembrane domain. Protein expression and interferon-γ dependent signaling were not detectable.

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Section: Flow Cytometric Analysis Of Ifn-γ R1 Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two Patients with Complete Defects in Interferon Gamma Receptor-Dependent Signaling

et al. 2007

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“…80 The IFNgR1 gene mutations are inherited as autosomal recessive traits and either abolish receptor expression 78,[80][81][82][83][84][85] or binding of the receptor to IFNg. [86][87] Partial IFNgR1 deficiency has also been described in two siblings, one of whom developed disseminated BCG infection and the other clinical tuberculosis. 88 In addition, there are two reports of disseminated mycobacterial infections caused by dominant IFNgR1 gene mutations.…”

Section: Familial Atypical Mycobacteriosis and Abnormal Ifng Signallingmentioning

confidence: 99%

Susceptibility to mycobacterial infections: the importance of host genetics

2003

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There is substantial evidence that host genetic factors are important in determining susceptibility to mycobacteria. Several different techniques have been used to identify the genes involved. Studies of an inbred strain of mice with increased susceptibility to mycobacteria, salmonella and leishmania infections led to the identification of the natural resistance-associated macrophage protein gene (Nramp1). Case-control studies have confirmed the importance of the human equivalent of this gene, NRAMP1, and have also suggested that the major histocompatibility complex and vitamin-D receptor genes may be involved in determining human susceptibility to mycobacteria. Studies of individuals with the rare condition of increased susceptibility to disseminated bacille Calmette-Guerin and other atypical mycobacterial infections have identified several abnormalities in the genes encoding the interferon gamma receptor (IFNgR) ligand binding chain, IFNgR signal transduction chain, IFNg signal transduction and activation of transcription-1, interleukin 12 receptor b1 subunit and interleukin 12 p40 subunit. A genome-wide linkage study has been performed to identify genes exerting a major effect on tuberculosis susceptibility in the general population. Linkages were found to markers on chromosomes 15 and X. Studies to identify the genes responsible are in progress.

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“…Molecular analysis showed that the child was homozygous for a C77F mutation in the exon 3 of IFNGR1 gene that results in complete lack of IFNgR1 expression. 9 Treatment with oral clarithromycin (15 mg/kg/day) and cotrimoxazole (7 mg trimethoprim/kg/ day) was initiated according to the M. fortuitum antibiogram and allowed rapid regression of symptoms (Hb ¼ 10.6 g/dl, WBC ¼ 8340/mm 3 , CRPo0.3 mg/dl). However, 6 months later, the child presented with recurrence of right inguinal and cervical lymphadenopathies, maculopapular rash and biological signs of active infection (Hb ¼ 7.8 mg/dl, WBC ¼ 8190/mm 3 , CRP ¼ 4.6 mg/dl).…”

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confidence: 99%

Successful hematopoietic stem cell transplantation in a child with active disseminated Mycobacterium fortuitum infection and interferon-γ receptor 1 deficiency

Chantrain

Bruwier

Brichard

et al. 2006

Bone Marrow Transplant

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In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ

Cited by 150 publications

References 40 publications

Two Patients with Complete Defects in Interferon Gamma Receptor-Dependent Signaling

Two Patients with Complete Defects in Interferon Gamma Receptor-Dependent Signaling

Susceptibility to mycobacterial infections: the importance of host genetics

Successful hematopoietic stem cell transplantation in a child with active disseminated Mycobacterium fortuitum infection and interferon-γ receptor 1 deficiency

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