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

Jürgen Klammt, David Neumann, Evelien F. Gevers, Shayne F. Andrew, I. David Schwartz, Denise Rockstroh, Roberto Colombo, Marco A. Sanchez, Doris Vokurkova, Julia Kowalczyk, Louise A. Metherell, Ron G. Rosenfeld, Roland Pfäffle, Mehul T. Dattani, Andrew Dauber and Vivian Hwa ()
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Jürgen Klammt: University Hospital Leipzig
David Neumann: Charles University, Prague
Evelien F. Gevers: Royal London Children’s Hospital, Barts Health NHS Trust
Shayne F. Andrew: University of Cincinnati College of Medicine
I. David Schwartz: Mercy Children’s Hospital and Mercy Clinic
Denise Rockstroh: University Hospital Leipzig
Roberto Colombo: Catholic University and IRCCS Policlinico Agostino Gemelli
Marco A. Sanchez: Oregon Health & Science University
Doris Vokurkova: Charles University, Prague
Julia Kowalczyk: Queen Mary University of London
Louise A. Metherell: Queen Mary University of London
Ron G. Rosenfeld: Oregon Health & Science University
Roland Pfäffle: University Hospital Leipzig
Mehul T. Dattani: Great Ormond Street Institute of Child Health
Andrew Dauber: University of Cincinnati College of Medicine
Vivian Hwa: University of Cincinnati College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04521-0

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