Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation

• Published in: Blood Vol. 118; no. 7; pp. 1806 - 1817
• Main Authors: Vairo, Donatella, Tassone, Laura, Tabellini, Giovanna, Tamassia, Nicola, Gasperini, Sara, Bazzoni, Flavia, Plebani, Alessandro, Porta, Fulvio, Notarangelo, Luigi D., Parolini, Silvia, Giliani, Silvia, Badolato, Raffaele
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 18.08.2011; Americain Society of Hematology
• Subjects: Biological and medical sciences; Child, Preschool; Cytomegalovirus Infections - complications; Cytomegalovirus Infections - genetics; Cytomegalovirus Infections - immunology; Hematologic and hematopoietic diseases; Humans; Interferon-alpha - immunology; Interferon-gamma - immunology; Killer Cells, Natural - immunology; Lung Diseases, Interstitial - complications; Lung Diseases, Interstitial - genetics; Lung Diseases, Interstitial - immunology; Medical sciences; Mutation; Mycobacterium Infections - complications; Mycobacterium Infections - genetics; Mycobacterium Infections - immunology; RNA Splicing; STAT1 Transcription Factor - genetics; Human; Transcription factor STAT1; Splicing; Hematology; Alpha interferon; Genetics; Mutation; Gamma interferon
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2011-01-330571

Subjects affected by Signal Transducer and Activator of Transcription 1 (STAT1) deficiency have lethal bacterial and viral infections. Complete STAT1 deficiency is inherited as an autosomal recessive disease; partial STAT1 deficiency is inherited as an autosomal recessive or autosomal dominant trait. Here, we report a patient who developed disseminated mycobacteriosis early in life and had several viral infections, including herpetic skin infection and interstitial pneumonia by cytomegalovirus with severe respiratory distress. Molecular analysis of STAT1 showed a novel homozygous mutation affecting a splice site, leading to exon 3 skipping and to synthesis of a lower molecular weight STAT1 protein. This mutation leads to marked reduction of STAT1 phosphorylation; the electromobility shift assay showed a complete defect of DNA-binding activity, which accounts for the complete impairment of peripheral blood mononuclear cell functional response to both IFN-γ and IFN-α. Moreover, analysis of natural killer cells showed a defective STAT1 phosphorylation in response to IFN-α and impaired basal cytolytic activity, suggesting that the STAT1-dependent pathway might be important for natural killer cell function. These results suggested that exon 3 skipping of STAT1 leads to abnormal signaling in response to IFN-γ and IFN-α, which is associated with susceptibility to intracellular pathogens and viruses.