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.

• Authors: Ariane Chapgier, Stéphanie Boisson-Dupuis, Emmanuelle Jouanguy, Guillaume Vogt, Jacqueline Feinberg, Ada Prochnicka-Chalufour, Armanda Casrouge, Kun Yang, Claire Soudais, Claire Fieschi, Orchidée Filipe Santos, Jacinta Bustamante, Capucine Picard, Ludovic de Beaucoudrey, Jean-François Emile, Peter D Arkwright, Robert D Schreiber, Claudia Rolinck-Werninghaus, Angela Rösen-Wolff, Klaus Magdorf, Joachim Roesler, Jean-Laurent Casanova
• Journal: PLoS genetics (PLoS Genet) Vol. 2 Issue 8 Pg. e131 (Aug 18 2006) ISSN: 1553-7404 [Electronic] United States
• PMID: 16934001 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• GAS1 protein, human
• GPI-Linked Proteins
• Interferon-Stimulated Gene Factor 3, gamma Subunit
• Interferon-alpha
• Membrane Proteins
• Mutant Proteins
• STAT1 Transcription Factor
• STAT1 protein, human
• Interferon-gamma

Topics

• Adolescent
• Adult
• Alleles
• Cell Cycle Proteins (metabolism)
• Cells, Cultured
• Child
• Child, Preschool
• DNA Mutational Analysis
• DNA-Binding Proteins (metabolism)
• Female
• GPI-Linked Proteins
• Gene Expression Regulation
• Genes, Dominant
• Genes, Recessive
• Heterozygote
• Humans
• Immunity, Active (genetics)
• Infant
• Interferon-Stimulated Gene Factor 3, gamma Subunit (metabolism)
• Interferon-alpha (metabolism)
• Interferon-gamma (metabolism)
• Male
• Membrane Proteins (metabolism)
• Models, Biological
• Models, Molecular
• Mutant Proteins (chemistry)
• Mutation
• Mycobacterium Infections (etiology, genetics)
• Pedigree
• Protein Binding
• STAT1 Transcription Factor (genetics, metabolism)
• Transcription, Genetic
• Transfection (methods)