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Nature communications v.9 no.1, 2018년, pp.2105 -    SCI SCIE
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Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation

Klammt, Jürgen    (Department of Women's and Child Health, University Hospital Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany   ); Neumann, David    (Department of Pediatrics, Faculty of Medicine, University Hospital Hradec Kralove, Charles University, Prague, 500 05 Hradec Kralove, Czech Republic   ); Gevers, Evelien F.    (Department of Pediatric Endocrinology, Royal London Children's Hospital, Barts Health NHS Trust, Whitechapel Road, London, E1 1 BB UK   ); Andrew, Shayne F.    (Division of Endocrinology, 240 Albert Sabin Way, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229 USA   ); Schwartz, I. David    (Mercy Kids Pediatric Endocrinology & Diabetes, Mercy Children's Hospital and Mercy Clinic, 1965 S. Fremont, Suite 260, Springfield, MO 65804 USA   ); Rockstroh, Denise    (Department of Women's and Child Health, University Hospital Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany   ); Colombo, Roberto    (Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University and IRCCS Policlinico Agostino Gemelli, Largo Francesco Vito 1, I-00168 Rome, Italy  ); Sanchez, Marco A.   Vokurkova, Doris   Kowalczyk, Julia   Metherell, Louise A.   Rosenfeld, Ron G.   Pfäffle, Roland   Dattani, Mehul T.   Dauber, Andrew   Hwa, Vivian  
  • 초록  

    Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system. Severe growth hormone insensitivity syndrome (GHIS) with immunodeficiency is caused by autosomal recessive mutations in STAT5B. Here the authors report heterozygous STAT5B mutations with dominant-negative effects, causing mild GHIS without immune defects.


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