title: Functional characterization of two new STAT3 mutations associated with hyper-IgE syndrome in a Mexican cohort.
abstract: Hyper-IgE syndrome (HIES) is an immunodeficiency disorder that is characterized by distinctive immunologic and non-immunologic manifestations. Although mutations in signal transducer and activator of transcription 3 (STAT3) have been associated with HIES, the exact nature of the relationship is unknown. Here, we characterized the functional activity of STAT3 and its mutations in 11 Mexican patients with autosomal dominant HIES. STAT3 phosphorylation was evaluated by flow cytometry, and in silico analyses were performed to estimate the impact of allelic mutations on the DNA binding and SH2 domains of the STAT3 protein. Electrophoretic mobility shift assays were used to assess whether the STAT3 mutants could bind to the consensus oligonucleotide target in vitro. Two novel mutations [g.58891A>T (Asn395Tyr) and g.59078A>T (Asn425Tyr)] as well as one possible somatic mosaicism were found in several of the patients who bore some remarkable features. However, there were no direct correlations between genotypes and HIES clinical features. STAT3 phosphorylation was found to be lower in the patient cohort than in healthy controls. Moreover, the mutated STAT3 proteins could bind to the Sp1, but not to the STAT3, consensus sequence. From these functional studies, the STAT3 mutations found in our patient cohort were concluded to be deleterious for normal STAT3 function.
authors: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.
authors: J C
authors: JC
authors: Alcántara-Montiel
authors: Hospital of High Specialties #25, IMSS, Monterrey, Nuevo Leon, Mexico.
authors: T
authors: T
authors: Staines-Boone
authors: Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico.
authors: G
authors: G
authors: López-Herrera
authors: Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico.
authors: F
authors: F
authors: Espinosa-Rosales
authors: Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico.
authors: S E
authors: SE
authors: Espinosa-Padilla
authors: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.
authors: R
authors: R
authors: Hernández-Rivas
authors: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.
authors: L
authors: L
authors: Santos-Argumedo
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015331:Cohort Studies; D016384:Consensus Sequence; D003710:Demography; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007589:Job Syndrome / Q000235:genetics*; D008297:Male; D008800:Mexico; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics*
chemical_list: D050796:STAT3 Transcription Factor; D019000:Phosphotyrosine
keywords: DNA-binding domain; SH2 domain; STAT3 phosphorylation; hyper-IgE syndrome