title: A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease.
abstract: BACKGROUND
  Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function.
  
  
  METHODS
  The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD.
  
  
  RESULTS
  Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the βD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-γ. The phosphorylated p.Phe646Ser, however, could not drive transcription.
  
  
  CONCLUSIONS
  A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 βD' strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.
authors.affiliation: Centro de Investigaciones Endocrinológicas (Consejo Nacional de Investigaciones Científicas y Técnicas), Ricardo Gutiérrez Children's Hospital, 1330 Buenos Aires, Argentina.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Scaglia
authors.forename: Alicia S
authors.initials: AS
authors.lastname: Martínez
authors.forename: Eva
authors.initials: E
authors.lastname: Feigerlová
authors.forename: Liliana
authors.initials: L
authors.lastname: Bezrodnik
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Gaillard
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Giovanni
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Ballerini
authors.forename: Héctor G
authors.initials: HG
authors.lastname: Jasper
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Heinrich
authors.forename: Peng
authors.initials: P
authors.lastname: Fang
authors.forename: Horacio M
authors.initials: HM
authors.lastname: Domené
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
mesh_terms: D004252:DNA Mutational Analysis; D004393:Dwarfism, Pituitary / Q000235:genetics*; D005260:Female; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics; D008171:Lung Diseases / Q000235:genetics; D020125:Mutation, Missense; D050799:STAT5 Transcription Factor / Q000235:genetics*; D013967:Thyroiditis, Autoimmune / Q000235:genetics*; D055815:Young Adult; D018909:src Homology Domains / Q000235:genetics
chemical_list: D050799:STAT5 Transcription Factor; D007334:Insulin-Like Growth Factor I