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Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.

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.

SUBMITTER: Chapgier A

PROVIDER: S-EPMC1550284 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.

Chapgier Ariane A Boisson-Dupuis Stéphanie S Jouanguy Emmanuelle E Vogt Guillaume G Feinberg Jacqueline J Prochnicka-Chalufour Ada A Casrouge Armanda A Yang Kun K Soudais Claire C Fieschi Claire C Santos Orchidée Filipe OF Bustamante Jacinta J Picard Capucine C de Beaucoudrey Ludovic L Emile Jean-François JF Arkwright Peter D PD Schreiber Robert D RD Rolinck-Werninghaus Claudia C Rösen-Wolff Angela A Magdorf Klaus K Roesler Joachim J Casanova Jean-Laurent JL

PLoS genetics 20060801 8

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 interf ...[more]

PMID: 16934001

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Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.

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Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.

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