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Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.

Chapgier, A; Boisson-Dupuis, S; Jouanguy, E; Vogt, G; Feinberg, J; Prochnicka-Chalufour, A; Casrouge, A; ... Casanova, JL; + view all (2006) Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genetics , 2 (8) e131 -. 10.1371/journal.pgen.0020131. Green open access

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Abstract

The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor-mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3-mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.

Type: Article
Title: Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.
Location: US
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.0020131
Publisher version: http://dx.doi.org/10.1371/journal.pgen.0020131
Language: English
Additional information: © 2006 Chapgier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC1550284
Keywords: Adolescent, Adult, Alleles, Cell Cycle Proteins, Cells, Cultured, Child, Child, Preschool, DNA Mutational Analysis, DNA-Binding Proteins, Female, GPI-Linked Proteins, Gene Expression Regulation, Genes, Dominant, Genes, Recessive, Heterozygote, Humans, Immunity, Active, Infant, Interferon-Stimulated Gene Factor 3, gamma Subunit, Interferon-alpha, Interferon-gamma, Male, Membrane Proteins, Models, Biological, Models, Molecular, Mutant Proteins, Mutation, Mycobacterium Infections, Pedigree, Protein Binding, STAT1 Transcription Factor, Transcription, Genetic, Transfection
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1356243
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