Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity

Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity

Copyright © 2019 Elsevier Inc. All rights reserved.

Détails bibliographiques
Publié dans:Clinical immunology (Orlando, Fla.). - 1999. - 210(2020) vom: 25. Jan., Seite 108316
Auteur principal: Jägle, Sabine (Auteur)
Autres auteurs: Heeg, Maximilian, Grün, Sarah, Rensing-Ehl, Anne, Maccari, Maria Elena, Klemann, Christian, Jones, Neil, Lehmberg, Kai, Bettoni, Claudia, Warnatz, Klaus, Grimbacher, Bodo, Biebl, Ariane, Schauer, Uwe, Hague, Rosie, Neth, Olaf, Mauracher, Andrea, Pachlopnik Schmid, Jana, Fabre, Alexandre, Kostyuchenko, Larysa, Führer, Marita, Lorenz, Myriam Ricarda, Schwarz, Klaus, Rohr, Jan, Ehl, Stephan
Format: Article en ligne
Langue:English
Publié: 2020
Accès à la collection:Clinical immunology (Orlando, Fla.)
Sujets:Journal Article Research Support, Non-U.S. Gov't STAT3 Transcription Factor
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520 |a Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations 
650 4 |a Journal Article 
650 4 |a Research Support, Non-U.S. Gov't 
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700 1 |a Heeg, Maximilian  |e verfasserin  |4 aut 
700 1 |a Grün, Sarah  |e verfasserin  |4 aut 
700 1 |a Rensing-Ehl, Anne  |e verfasserin  |4 aut 
700 1 |a Maccari, Maria Elena  |e verfasserin  |4 aut 
700 1 |a Klemann, Christian  |e verfasserin  |4 aut 
700 1 |a Jones, Neil  |e verfasserin  |4 aut 
700 1 |a Lehmberg, Kai  |e verfasserin  |4 aut 
700 1 |a Bettoni, Claudia  |e verfasserin  |4 aut 
700 1 |a Warnatz, Klaus  |e verfasserin  |4 aut 
700 1 |a Grimbacher, Bodo  |e verfasserin  |4 aut 
700 1 |a Biebl, Ariane  |e verfasserin  |4 aut 
700 1 |a Schauer, Uwe  |e verfasserin  |4 aut 
700 1 |a Hague, Rosie  |e verfasserin  |4 aut 
700 1 |a Neth, Olaf  |e verfasserin  |4 aut 
700 1 |a Mauracher, Andrea  |e verfasserin  |4 aut 
700 1 |a Pachlopnik Schmid, Jana  |e verfasserin  |4 aut 
700 1 |a Fabre, Alexandre  |e verfasserin  |4 aut 
700 1 |a Kostyuchenko, Larysa  |e verfasserin  |4 aut 
700 1 |a Führer, Marita  |e verfasserin  |4 aut 
700 1 |a Lorenz, Myriam Ricarda  |e verfasserin  |4 aut 
700 1 |a Schwarz, Klaus  |e verfasserin  |4 aut 
700 1 |a Rohr, Jan  |e verfasserin  |4 aut 
700 1 |a Ehl, Stephan  |e verfasserin  |4 aut 
773 0 8 |i Enthalten in  |t Clinical immunology (Orlando, Fla.)  |d 1999  |g 210(2020) vom: 25. Jan., Seite 108316  |w (DE-627)NLM098196855  |x 1521-7035  |7 nnas 
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856 4 0 |u http://dx.doi.org/10.1016/j.clim.2019.108316  |3 Volltext 
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