title: Growth hormone/JAK-STAT axis signal-transduction defect. A novel treatable cause of growth failure.
abstract: Primary cultured fibroblasts of four patients with idiopathic short stature and severe growth delay, which displayed normal growth hormone receptor expression presented a reduced ability for activation of signal transducer and activator of transcription-3 (STAT3). Impaired STAT3 activation was accompanied by cell-cycle arrest at the Go /G1 phase. Increased levels of the cyclin-dependent kinase inhibitor, p21(WAF/CIPI), and reduced levels of cyclins were also detected in these patients. High concentrations of human growth hormone (1000 ng x mL(-1)) added to the culture medium induced activation of STAT3 and reduced the levels of p21(WAF/CIPI) in the fibroblasts of the four idiopathic short stature children. Treatment of these children with exogenous human growth hormone significantly augmented their growth velocity. Overall, our study provides the first evidence linking the idiopathic short stature phenotype with a functional aberration in the growth hormone signal transduction cascade which can be successfully overcome by exposure to high doses of growth hormone.
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University of Patras School of Medicine, Greece.
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Rojas-Gil
authors.forename: Panos G
authors.initials: PG
authors.lastname: Ziros
authors.forename: Leonor
authors.initials: L
authors.lastname: Diaz
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
authors.forename: Efthimia K
authors.initials: EK
authors.lastname: Basdra
authors.forename: Theodore K
authors.initials: TK
authors.lastname: Alexandrides
authors.forename: Zvi
authors.initials: Z
authors.lastname: Zadik
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papathanassopoulou
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Beratis
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
authors.forename: Bessie E
authors.initials: BE
authors.lastname: Spiliotis
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D006130:Growth Disorders / Q000209:etiology / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D050791:STAT Transcription Factors; D013006:Growth Hormone; D011494:Protein Kinases