Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants

Kagawa, Reiko; Fujiki, Ryoji; Tsumura, Miyuki; Sakata, Sonoko; Nishimura, Shiho; Itan, Yuval; Kong, Xiao‐Fei; Kato, Zenichiro; Ohnishi, Hiroyuki; Hirata, Osamu; Saitô, Satoshi; Ikeda, Maiko; Baghdadi, Jamila El; Bousfiha, Aziz; Fujiwara, Kaori; Oleastro, Matías; Yancoski, Judith; Pérez, Laura; Danielian, Silvia; Ailal, Fatima; Takada, Hidetoshi; Hara, Toshiro; Puel, Anne; Boisson–Dupuis, Stéphanie; Bustamante, Jacinta; Casanova, Jean‐Laurent; Ohara, Osamu; Okada, Satoshi; Kobayashi, Masao

doi:10.1016/j.jaci.2016.09.035

Cited by 48 publications

(75 citation statements)

References 63 publications

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“…Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a). Over this period, the genetic dissection of MSMD in these patients has revealed this condition to be caused by inborn errors of interferon (IFN)‐γ immunity . These findings confirm that IFN‐γ, first described in 1965 as an antiviral IFN, is actually the macrophage‐activating factor, as shown in 1983 .…”

Section: Introductionsupporting

confidence: 61%

“…Since the last comprehensive review on MSMD in 2014, three new genetic disorders have been reported, caused by mutations of TYK2 and SPPL2A, (two novel genetic etiologies) and IFNGR2 (a novel allelic form). Moreover, new mutations associated with the other 18 disorders have also been reported . We also discuss here two recently reported syndromic forms of MSMD: AR RORγ/RORγT and Janus kinase (JAK)1 deficiencies .…”

Section: Introductionmentioning

confidence: 80%

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Mendelian susceptibility to mycobacterial disease: 2014–2018 update

et al. 2018

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Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-c immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-cR2 deficiency, and (4) two forms of syndromic MSMD: RORc/RORcT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 80%

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

et al. 2018

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“…BCG disease has been reported in CGD patients, but cases of M. avium complex infection have rarely been reported in this population. Moreover, these 2 mycobacterial infections are probably not related to p40 phox deficiency in P19, because this patient also carries a dominant-negative STAT1 mutation responsible for MSMD (47 The production of intracellular ROS by neutrophils, monocytes, and NB4 cells was analyzed with DHR (Thermo Fisher Scientific), as previously described (66). We added 0.5 μM DHR in DMSO to 2.5 × 10 6 neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…This same patient subsequently suffered from meningitis caused by Mycobacterium avium. Interestingly, this patient was also heterozygous for a dominant-negative LOF mutation of STAT1, which is responsible for MSMD (47). Four asymptomatic children, aged 1, 3, 8, and 10 years at diagnosis of p40 phox deficiency, were healthy controls, and unlike MDDCs from classic CGD patients ( Figure 5B).…”

Section: Peripheral But Not Invasive Infections In Patients With P40mentioning

confidence: 99%

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Geer¹,

Nieto-Patlán²,

Kuhns³

et al. 2018

Journal of Clinical Investigation

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108

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Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40 phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40 phox -deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMAinduced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40 phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD. phox -deficient patient is compound heterozygous for a premature stop codon and a missense mutation in the PX domain that compromises binding to PI(3)P, which results in the impairment of neutrophil phagocytosis-induced oxidase activity (26). As in classic CGD neutrophils, intracellular oxidant production after stimulation with serum-opsonized zymosan (SOZ), IgG beads, or serumopsonized Staphylococcus aureus is impaired in the patient's neutrophils, and S. aureus killing is also defective (20,26,30). However, in this patient, unlike in classic CGD patients, the production of O 2 -by neutrophils in response to stimulation with PMA or formyl-methionyl-leucyl-phenylalanine (fMLF) is normal (26). The killing of S. aureus by neutrophils is also impaired in p40 phox deficiency and classic CGD are largely unknown. Here, we describe the characteristics of 24 patients from 12 families in 8 countries with biallelic mutations of NCF4. The Journal of Clinical Investigation R E S E A R C H A R T I C L E

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“…Clinical presentation is in most of the cases multifocal MOM caused by environmental mycobacteria (EM), mainly M. avium or BCG. MOM is a frequent manifestation in AD IFN- γ R1 or AD STAT1-deficient patients, all but one as disseminated osteomyelitis [34-38]. Additionally, patients with autosomal recessive (AR) IFN- γ R1 deficiency have been described with MOM as part of disseminated mycobacterial disease.…”

Section: Discussionmentioning

confidence: 99%

Impaired IL-12- and IL-23-Mediated Immunity Due to IL-12Rβ1 Deficiency in Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease

et al. 2018

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Purpose. Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette–Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM). Methods. In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran with disseminated BCG disease. We evaluated the patients’ whole blood cell response to IL-12 and IFN-γ, IL-12Rβ1 expression on T-cell blasts, and sequenced candidate genes. Results. We reported four patients from Isfahan, Iran, ranging from 3 months to 26 years old, who had impaired IL-12 signaling. All patients suffered from BCG infectious diseases. One of them presented mycobacterial osteomyelitis as a form of infection. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rβ1 was completely abolished in the four patients with IL12RB1 mutations. Conclusions. IL-12Rβ1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321X mutant IL-12Rβ1 protein. Mycobacterial osteomyelitis is another type of location of mycobacterial infection in an IL-12Rβ1-deficient patient, notified for the first time in this study.

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Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants

Cited by 48 publications

References 63 publications

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Impaired IL-12- and IL-23-Mediated Immunity Due to IL-12Rβ1 Deficiency in Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease

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