
<lom:lom xmlns:lom="https://oer-repo.uibk.ac.at/lom" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="https://oer-repo.uibk.ac.at/lom/latest https://w3id.org/oerbase/profiles/lomuibk/latest/schemas/lom-uibk.xsd">
  
<lom:general>
  
<lom:identifier>
  
<lom:catalog>phaidra.vetmeduni.ac.at</lom:catalog>

  
<lom:entry>
  
<lom:langstring xml:lang="x-none">o:5455</lom:langstring>

  
</lom:entry>

  
</lom:identifier>

  
<lom:identifier>
  
<lom:catalog>DOI</lom:catalog>

  
<lom:entry>
  
<lom:langstring xml:lang="x-none">10.1016/j.jaci.2025.12.993</lom:langstring>

  
</lom:entry>

  
</lom:identifier>

  
<lom:title>
  
<lom:langstring xml:lang="en">Somatic STAT5BN642H mutations shape variable immune landscapes resulting in heterogenous immune diseases</lom:langstring>

  
</lom:title>

  
<lom:description>
  
<lom:langstring xml:lang="en">Background

Inborn errors of immunity are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking inborn errors of immunity. While early postzygotic mosaicism is the predominant mechanism, genetic variants causing a selective advantage to hematopoietic progenitors and/or mature immune cells may cause immune dysregulation and initiate disease at any age. Somatic mosaicism for STAT5BN642H was linked to severe allergic disease in infancy, but its full clinical spectrum and underlying mechanisms remain incompletely defined.

Objective

We elucidated how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function, and clinical phenotypes.

Methods

We investigated 3 new patients—including one adult—with STAT5BN642H mosaicism using deep sequencing, flow and mass cytometry, and functional immune assays. Mutant cell distribution was mapped across blood lineages. A mouse model with mosaic STAT5BN642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes.

Results

Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2–mediated proliferation, effector differentiation, and oligoclonal T-cell expansions. In mice, a few mutant hematopoietic stem cells reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T-cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients.
Conclusion
A single somatic variant in a few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.</lom:langstring>

  
</lom:description>

  
<lom:language>eng</lom:language>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">STAT5B</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">somatic mosaicism</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">hematopoietic stem cells</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">clonal hematopoiesis</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">immune dysregulation</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">T-cell lymphoproliferation</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">autoimmunity</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">atopy</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">mTOR inhibition</lom:langstring>

  
</lom:keyword>

  
</lom:general>

  
<lom:lifecycle>
  
<lom:datetime>2026-08-25T08:12:15.784Z</lom:datetime>

  
<lom:contribute>
  
<lom:role>
  
<lom:source>
  
<lom:langstring xml:lang="x-none">LOMv1.0</lom:langstring>

  
</lom:source>

  
<lom:value>
  
<lom:langstring xml:lang="x-none">Author</lom:langstring>

  
</lom:value>

  
</lom:role>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Grün;Sarah;
FN:Sarah Grün
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Rensing-Ehl;Anne;
FN:Anne Rensing-Ehl
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Suske;Tobias;
FN:Tobias Suske
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Wolter-Mess;Julian;
FN:Julian Wolter-Mess
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Gehrig;Jonathan;
FN:Jonathan Gehrig
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Mann;Jasmin;
FN:Jasmin Mann
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:König;Christoph;
FN:Christoph König
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Hauri;Mathias;
FN:Mathias Hauri
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Heeg;Maximilian;
FN:Maximilian Heeg
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Leahy;Timothy Ronan;
FN:Timothy Ronan Leahy
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Genevieve;David;
FN:David Genevieve
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Gaillard;Jean-Baptiste;
FN:Jean-Baptiste Gaillard
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Broly;Martin;
FN:Martin Broly
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Bourdin;Arnaud;
FN:Arnaud Bourdin
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Castro;Carla;
FN:Carla Castro
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Seidel;Lea;
FN:Lea Seidel
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Bengsch;Bertram;
FN:Bertram Bengsch
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Aichele;Peter;
FN:Peter Aichele
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Weißert;Kristoffer;
FN:Kristoffer Weißert
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Fernandez-Orth;Juncal;
FN:Juncal Fernandez-Orth
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Schipperges;Vincent;
FN:Vincent Schipperges
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Andrieux;Geoffroy;
FN:Geoffroy Andrieux
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Boerries;Melanie;
FN:Melanie Boerries
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Cabezas-Wallscheid;Nina;
FN:Nina Cabezas-Wallscheid
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Erlacher;Miriam;
FN:Miriam Erlacher
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Elling;Roland;
FN:Roland Elling
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Speckmann;Carsten;
FN:Carsten Speckmann
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Heller;Lara;
FN:Lara Heller
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Schulte;Björn;
FN:Björn Schulte
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Lorenz;Myriam;
FN:Myriam Lorenz
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Schwarz;Klaus;
FN:Klaus Schwarz
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Moriggl;Richard;
FN:Richard Moriggl
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Ehl;Stephan;
FN:Stephan Ehl
X-ORCID:https://orcid.org/0000-0002-9265-2721
END:VCARD</lom:vcard>

  
</lom:centity>

  
</lom:contribute>

  
</lom:lifecycle>

  
<lom:educational>
  
<lom:learningresourcetype>
  
<lom:source>
  
<lom:langstring xml:lang="x-none">https://w3id.org/kim/hcrt/scheme</lom:langstring>

  
</lom:source>

  
<lom:id>https://w3id.org/kim/hcrt/text</lom:id>

  
<lom:entry>
  
<lom:langstring xml:lang="de">Textdokument</lom:langstring>

  
<lom:langstring xml:lang="en">Text</lom:langstring>

  
</lom:entry>

  
</lom:learningresourcetype>

  
</lom:educational>

  
<lom:rights>
  
<lom:copyrightandotherrestrictions>
  
<lom:source>
  
<lom:langstring xml:lang="x-none">LOMv1.0</lom:langstring>

  
</lom:source>

  
<lom:value>
  
<lom:langstring xml:lang="x-none">yes</lom:langstring>

  
</lom:value>

  
</lom:copyrightandotherrestrictions>

  
<lom:description>
  
<lom:langstring xml:lang="x-t-cc-url">https://creativecommons.org/licenses/by/4.0</lom:langstring>

  
</lom:description>

  
</lom:rights>

  
<lom:technical>
  
<lom:format>application/pdf</lom:format>

  
<lom:size>2740254</lom:size>

  
<lom:location>https://phaidra.vetmeduni.ac.at/o:5455</lom:location>

  
<lom:thumbnail>
  
<lom:url>https://phaidra.vetmeduni.ac.at/api/object/o:5455/thumbnail</lom:url>

  
</lom:thumbnail>

  
</lom:technical>

  
<lom:classification>
  
<lom:purpose>
  
<lom:source>
  
<lom:langstring xml:lang="x-none">LOMv1.0</lom:langstring>

  
</lom:source>

  
<lom:value>
  
<lom:langstring xml:lang="x-none">discipline</lom:langstring>

  
</lom:value>

  
</lom:purpose>

  
</lom:classification>

  
</lom:lom>