A novel kindred with inherited STAT2 deficiency and severe viral illness

IFN-α-induced IFN-stimulated gene factor 3 complex-mediated binding to IFN-α sequence response element was specifically abolished in P2, whereas IFN-γ and IFN-α induced gamma activating factor-mediated (gamma-activating sequences interaction were not affected; see Fig E3 in this article's Onlin...

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Published in:Journal of allergy and clinical immunology 2017-06, Vol.139 (6), p.1995-1997.e9
Main Authors: Moens, Leen, PhD, Van Eyck, Lien, MSc, MD, Jochmans, Dirk, PhD, Mitera, Tania, BSc, Frans, Glynis, MPharm, Bossuyt, Xavier, MD, PhD, Matthys, Patrick, PhD, Neyts, Johan, PhD, Ciancanelli, Michael, PhD, Zhang, Shen-Ying, MD, PhD, Gijsbers, Rik, PhD, Casanova, Jean-Laurent, MD, PhD, Boisson-Dupuis, Stephanie, PhD, Meyts, Isabelle, MD, PhD, Liston, Adrian, PhD
Format: Article
Language:English
Subjects:
Alleles
Allergy and Immunology
Cerebrospinal fluid
Cytomegalovirus
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Human papillomavirus
Humans
Infections
Interferon
Male
Mumps
Mutation
Pedigree
Repositories
Respiratory syncytial virus
Severity of Illness Index
Siblings
Stat2 protein
STAT2 Transcription Factor - deficiency
Vaccines
Viral diseases
Viral infections
Virus Diseases - diagnosis
Virus Diseases - etiology
Whole Genome Sequencing
α-Interferon
γ-Interferon
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Summary:IFN-α-induced IFN-stimulated gene factor 3 complex-mediated binding to IFN-α sequence response element was specifically abolished in P2, whereas IFN-γ and IFN-α induced gamma activating factor-mediated (gamma-activating sequences interaction were not affected; see Fig E3 in this article's Online Repository at www.jacionline.org). [...]interferon-inducible genes (MxA, ISG15, and OAS1) were not upregulated following IFN-α stimulation in the patient's primary fibroblasts (Fig 1, D; see Fig E4 in this article's Online Repository at www.jacionline.org). [...]lentiviral transduction of wild-type STAT2 in primary fibroblasts of the patient restored STAT2 expression, IFN-α-induced STAT2 phosphorylation (Fig 1, F), and upregulation of interferon-inducible target genes (MxA, ISG15, and OAS1) (Fig 1, G-I). Similar diversity in presentation has been reported in other innate immune disorders such as TLR3 deficiency.7 Impaired response to IFN-α and life-threatening viral diseases in STAT2-deficient patients are reminiscent of the phenotype of patients with complete autosomal recessive STAT1 deficiency, who additionally suffer from severe infections with weakly virulent Mycobacteria and other intracellular bacteria.3 The STAT1-deficiency viral phenotype, however, seems more severe and broad than that of STAT2 deficiency, as out of the 6 identified patients, 4 died in early infancy due to herpes simplex virus-1, cytomegalovirus, or antiepileptic drugs; A&W, alive and well; BAL, broncho-alveolar lavage; CSF, cerebrospinal fluid; FS, febrile syndrome; HPV, human papilloma virus; HSV, herpes simplex virus; IVIG, intravenous immunoglobulin substitution; MMR, measles-mumps-rubella vaccine; NA, not applicable; ND, not done; RSV, respiratory syncytial virus; VZV, Varicella zoster virus. Patient Mutation Phenotype Virus Treatment Outcome at latest follow-up reported 1E7 c.381+5G>C 18 mo:...
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2016.10.033