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

Nature Communications
Jürgen KlammtVivian Hwa

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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Citations

Sep 29, 2018·Endocrine Reviews·Helen L StorrVivian Hwa
Mar 14, 2019·Archives of Endocrinology and Metabolism·Gabriela A VasquesAlexander A L Jorge
Nov 9, 2018·Current Opinion in Pediatrics·Liliana BezrodnikMaría Soledad Caldirola
Nov 14, 2019·Cancers·Elvin D de AraujoPatrick T Gunning
Sep 4, 2019·Journal of Clinical Immunology·Peter GeorgievTalal A Chatila
Jul 3, 2019·NPJ Genomic Medicine·Salla KeskitaloMarkku Varjosalo
Jan 16, 2020·Archives of Endocrinology and Metabolism·Gabriela A VasquesAlexander A L Jorge
Sep 27, 2019·Frontiers in Endocrinology·Jesús ArgenteRoland Pfäffle
Oct 8, 2020·Reviews in Endocrine & Metabolic Disorders·Martin O SavagePhilippe F Backeljauw
Oct 9, 2020·Reviews in Endocrine & Metabolic Disorders·Vivian HwaRon G Rosenfeld
Oct 23, 2020·Journal of Clinical Immunology·Corinne L FoleyVivian Hwa
Dec 18, 2020·Frontiers in Pediatrics·Magda Carneiro-SampaioAntonio Coutinho
Jan 11, 2020·Haematologica·Rodrigo Prieto-BermejoÁngel Hernández-Hernández
Jan 28, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Pieter SchellekensDjalila Mekahli
Dec 15, 2020·Frontiers in Endocrinology·Ger J StrousJan A Mol
Oct 31, 2020·Molecular and Cellular Endocrinology·Vivian Hwa
May 9, 2021·Trends in Immunology·Gökhan CildirDamon J Tumes
Aug 2, 2021·Molecular and Cellular Endocrinology·Renata C ScalcoAlexander A L Jorge
Oct 21, 2021·Current Opinion in Pediatrics·Yesim DemirdagJoyce E Yu
Jan 13, 2022·Clinical Reviews in Allergy & Immunology·Margaret T RedmondBenjamin T Prince

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Datasets Mentioned

BETA
SCV000681436
SCV000680478
SCV000693651

Methods Mentioned

BETA
immunoprecipitation
nuclear translocation
electrophoretic mobility shift assays
electrophoretic mobility shift assay
biopsy
PCR
biopsies
transfection
co-immunoprecipitation
Assay

Software Mentioned

GraphPad Prism
ClinVar
SoftWoRx
Genome Analysis Toolkit ( GATK )
IntegenX

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