title: Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation.
abstract: 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.
authors.affiliation: Pediatric Clinic and A. Nocivelli Institute of Molecular Medicine, Brescia, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Vairo
authors.forename: Laura
authors.initials: L
authors.lastname: Tassone
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tabellini
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.forename: Sara
authors.initials: S
authors.lastname: Gasperini
authors.forename: Flavia
authors.initials: F
authors.lastname: Bazzoni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Fulvio
authors.initials: F
authors.lastname: Porta
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Silvia
authors.initials: S
authors.lastname: Parolini
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D002675:Child, Preschool; D003586:Cytomegalovirus Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D017563:Lung Diseases, Interstitial / Q000150:complications / Q000235:genetics / Q000276:immunology; D009154:Mutation; D009164:Mycobacterium Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology; D012326:RNA Splicing; D050794:STAT1 Transcription Factor / Q000235:genetics*
chemical_list: D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma