Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome

Kong, Xiao‐Fei; Worley, Lisa; Rinchai, Darawan; Bondet, Vincent; Jithesh, Puthen V.; Goulet, Marie; Nonnotte, Emilie; Rebillat, Anne Sophie; Conte, Martine; Mircher, Clotilde; Gürtler, Nicolas; Liu, Luyan; Migaud, Mélanie; Elanbari, Mohammed; Habib, Tanwir; Cindy, S.; Bustamante, Jacinta; Abel, Laurent; Ravel, Aimé; Lyonnet, Stanislas; Münnich, Arnold; Duffy, Darragh; Chaussabel, Damien; Casanova, Jean‐Laurent; Tangye, Stuart G.; Boisson–Dupuis, Stéphanie; Puel, Anne

doi:10.1007/s10875-020-00803-9

Cited by 46 publications

(59 citation statements)

References 45 publications

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“…Six patients had phagocyte defects: 4 with X-linked (variants in CYBB [P8, P88, and P92]) or recessive (bialleic variants in NCF2 [P89]) chronic granulomatous disease (CGD); 1 (P88) was treated with cyclosporin ( Fig 1 and Table II ). Fourteen patients had combined immunodeficiencies (CIDs), including 10 with syndromic features: Di George syndrome (P27); trisomy 21 (Down syndrome [P15, P17, and P26]), 24 , 25 Wiskott-Aldrich syndrome (P16: 3 months post–hematopoietic stem cell transplantation [HSCT]; P35: 5 months post–gene therapy), ARPC1B deficiency (P25), hyper-IgE syndrome due to heterozygous dominant negative variants in STAT3 (P77 and P78), or biallelic variants in PGM3 (P76). Other patients had pathogenic biallelic variants in ZAP70 (P73) or IFNGR2 (P38), or heterozygous gain-of-function variant in STAT1 (P93).…”

Section: Resultsmentioning

confidence: 99%

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Meyts

Bucciol

Quinti

et al. 2021

Journal of Allergy and Clinical Immunology

299

540

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Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

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Section: Resultsmentioning

confidence: 99%

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Meyts

Bucciol

Quinti

et al. 2021

Journal of Allergy and Clinical Immunology

299

540

View full text Add to dashboard Cite

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“…An important outcome of our study was the observation that small-molecule mediated degradation of BRD9, using dBRD9-A 43,44 , limits IFN-induced expression of certain ISGs in multiple cell-types. This finding could have implications for the consideration of BRD9 as a viable therapeutic target in the treatment of some autoinflammatory interferonopathies 9–17 , particularly under specific circumstances where broad targeting of JAK-mediated signaling may not be appropriate 21,22 . Furthermore, we also note that BRD9 inhibition (or degradation) is an attractive therapeutic aim for the treatment of several cancers 24,44,60 .…”

Section: Discussionmentioning

confidence: 99%

“…It is essential that the IFN system is tightly regulated at the molecular level to prevent exuberant proinflammatory responses following infection 6–8 . Furthermore, uncontrolled activation of the IFN system caused by loss- or gain- of-function mutations in key regulators of the IFN pathway can be associated with aberrantly high levels of circulating IFNs and/or the constitutive expression of ISGs, leading to a broad range of autoinflammatory disorders known as interferonopathies 9–17 . Proposed treatments for interferonopathies include JAK inhibitors (such as baricitinib 18 , ruxolitinib 19 or tofacitinib 20 ) to limit the signaling action of high levels of constitutively circulating IFN or inappropriate JAK-STAT regulation.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide CRISPR Screening Identifies BRD9 as a Druggable Component of Interferon-Stimulated Gene Expression and Antiviral Activity

Börold

Eletto

Busnadiego

et al. 2021

Preprint

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Transient interferon (IFN) induction of IFN-stimulated genes (ISGs) creates a formidable protective antiviral state. However, loss of appropriate control mechanisms can result in constitutive pathogenic ISG upregulation. Here, we used genome-wide loss-of-function screening to establish genes critical for IFN signaling, identifying all expected members of the JAK-STAT pathway and the previously unappreciated bromodomain-containing protein 9 (BRD9), a defining subunit of non-canonical BAF (ncBAF) chromatin remodeling complexes. Genetic knock-out or small-molecule mediated degradation of BRD9 limited IFN-induced expression of a subset of ISGs in multiple cell-types, and prevented IFN from exerting full antiviral activity against several RNA and DNA viruses. Mechanistically, BRD9 acts at the level of ISG transcription, exhibits a proximal association with STAT2 following IFN stimulation, and relies on its intact acetyl-binding bromodomain and unique ncBAF scaffolding function for activity. Given its druggability, BRD9 may be an attractive target for dampening constitutive ISG expression under certain pathogenic autoinflammatory conditions.

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“…These data might lead to the hypothesis that mutation and common polymorphisms (single nucleotide polymorphisms, SNPs) of gene, such as IFN receptor gene SNP, mapping at HSA21 might be responsible for the heterogeneity of expression of the diverse organ/system anomalies characterizing the Down syndrome phenotypes, such as CHDs. Increased expression of these receptors in patients with DS has been demonstrated to contribute to autoimmune diseases [18]. Impaired activation of IFN signaling has also been reported in individuals with DS and periodontitis [19].…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to Heart Defects in Down Syndrome Is Associated with Single Nucleotide Polymorphisms in HAS 21 Interferon Receptor Cluster and VEGFA Genes

Balistreri

Ammoscato

Scola

et al. 2020

Genes

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Background: Congenital heart defects (CHDs) are present in about 40–60% of newborns with Down syndrome (DS). Patients with DS can also develop acquired cardiac disorders. Mouse models suggest that a critical 3.7 Mb region located on human chromosome 21 (HSA21) could explain the association with CHDs. This region includes a cluster of genes (IFNAR1, IFNAR2, IFNGR2, IL10RB) encoding for interferon receptors (IFN-Rs). Other genes located on different chromosomes, such as the vascular endothelial growth factor A (VEGFA), have been shown to be involved in cardiac defects. So, we investigated the association between single nucleotide polymorphisms (SNPs) in IFNAR2, IFNGR2, IL10RB and VEGFA genes, and the presence of CHDs or acquired cardiac defects in patients with DS. Methods: Individuals (n = 102) with DS, and age- and gender-matched controls (n = 96), were genotyped for four SNPs (rs2229207, rs2834213, rs2834167 and rs3025039) using KASPar assays. Results: We found that the IFNGR2 rs2834213 G homozygous genotype and IL10RB rs2834167G-positive genotypes were more common in patients with DSand significantly associated with heart disorders, while VEGFA rs3025039T-positive genotypes (T/*) were less prevalent in patients with CHDs. Conclusions: We identified some candidate risk SNPs for CHDs and acquired heart defects in DS. Our data suggest that a complex architecture of risk alleles with interplay effects may contribute to the high variability of DS phenotypes.

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Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome

Cited by 46 publications

References 45 publications

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Genome-Wide CRISPR Screening Identifies BRD9 as a Druggable Component of Interferon-Stimulated Gene Expression and Antiviral Activity

Susceptibility to Heart Defects in Down Syndrome Is Associated with Single Nucleotide Polymorphisms in HAS 21 Interferon Receptor Cluster and VEGFA Genes

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