Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation

Nat Commun. 2018 May 29;9(1):2105. doi: 10.1038/s41467-018-04521-0.

Jürgen Klammt ¹, David Neumann ², Evelien F Gevers ³ ⁴, Shayne F Andrew ⁵, I David Schwartz ⁶, Denise Rockstroh ¹, Roberto Colombo ⁷ ⁸, Marco A Sanchez ⁹, Doris Vokurkova ¹⁰, Julia Kowalczyk ⁴, Louise A Metherell ⁴, Ron G Rosenfeld ¹¹, Roland Pfäffle ¹, Mehul T Dattani ¹², Andrew Dauber ⁵, Vivian Hwa ¹³

Affiliations

1 Department of Women's and Child Health, University Hospital Leipzig, Liebigstrasse 20a, 04103, Leipzig, Germany.
2 Department of Pediatrics, Faculty of Medicine, University Hospital Hradec Kralove, Charles University, Prague, 500 05, Hradec Kralove, Czech Republic.
3 Department of Pediatric Endocrinology, Royal London Children's Hospital, Barts Health NHS Trust, Whitechapel Road, London, E1 1 BB, UK.
4 Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, First Floor North, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
5 Division of Endocrinology, 240 Albert Sabin Way, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA.
6 Mercy Kids Pediatric Endocrinology & Diabetes, Mercy Children's Hospital and Mercy Clinic, 1965 S. Fremont, Suite 260, Springfield, MO, 65804, USA.
7 Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University and IRCCS Policlinico Agostino Gemelli, Largo Francesco Vito 1, I-00168, Rome, Italy.
8 Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy.
9 Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
10 Department of Clinical Immunology and Allergology, Faculty of Medicine, University Hospital Hradec Kralove, Charles University, Prague, 500 05, Hradec Kralove, Czech Republic.
11 Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
12 Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London, Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
13 Division of Endocrinology, 240 Albert Sabin Way, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA. Vivian.Hwa@cchmc.org.

PMID: 29844444 DOI: 10.1038/s41467-018-04521-0

Abstract

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.

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