Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 7 min ago
Peer-reviewedCC BY 4.0Frontiers in Immunology

Hypomorphic biallelic LIFR variants define a multisystem disorder with survival beyond infancy and hyperinflammatory vulnerability

  • Madeleine Schmidt1
  • Puyan Rafii2
  • Aisha AlShamsi3
  • Giovanni Zifarelli4
  • Maxi Leona Wiese1,5
  • Joachim David Steiner5,6,7
  • Sarah Kreuz5
  • Robert Walter Körner1
  • Clara Velmans8
  • Christian Netzer8
  • Oliver Semler1
  • Majid Alfadhel9,10
27 more authors
  • Hiba Abu Khalil10
  • Ezgi Susam11
  • Sujatha Jagadeesh12
  • Beena Suresh12
  • Nicolai Kohlschmidt13
  • Philip M. Boone14
  • Sheela Nampoothiri15
  • Radhakrishnan Periyasamy16
  • Katta M. Girisha16
  • Andreas Hahn17
  • Adela Chirita-Emandi18
  • Raphael Hirtz19
  • Kai O. Hensel19
  • Peter Bauer4
  • Konstantin L. Makridis20,21,22,23
  • Angela M. Kaindl20,21,22,23
  • Ilja Dubinski24
  • Jürgen-Christoph von Kleist-Retzow1
  • Gregor Dückers25
  • Reem Elfeky26
  • Maaike Kusters26
  • Tim Niehues25,27
  • Vivien Béziat28
  • Heinz Jungbluth1,29,30
  • Adam Antebi5
  • Jürgen Scheller2
  • Hormos S. Dafsari1,5,30,31,32
32 affiliations
  1. 1Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne
  2. 2Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
  3. 3Division of Genetics and Metabolic, Department of Paediatrics, Tawam Hospital
  4. 4CENTOGENE GmbH
  5. 5Max-Planck-Institute for Biology of Ageing and Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
  6. 6Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne
  7. 7Center of Excellence in Nephrology, University Hospitals Aachen
  8. 8Institute of Human Genetics, Faculty of Medicine and University Hospital, University of Cologne
  9. 9Medical Genomic Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA)
  10. 10Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children’s Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA)
  11. 11Division of Medical Genetics, Sakarya Research and Training Hospital
  12. 12Department of Clinical Genetics & Genetic Counseling Mediscan Systems
  13. 13Institute of Clinical Genetics and Tumor Genetics, Medizinisches Versorgungszentrum (MVZ)
  14. 14Division of Genetics and Genomics, Boston Children’s Hospital
  15. 15Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre
  16. 16Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India and Suma Genomics Private Limited
  17. 17Department of Child Neurology, University Hospital
  18. 18Genetics Department, Center for Genomic Medicine, University of Medicine and Pharmacy “Victor Babes”
  19. 19Witten/Herdecke University, Department of Pediatrics, Faculty of Health, Helios University Hospital Wuppertal, Children’s Hospital
  20. 20Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin
  21. 21Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin
  22. 22Institute of Cell- and Neurobiology, Charité – Universitätsmedizin Berlin
  23. 23Section Central Nervous System (CNS) Development and Neurologic Disease, Partner Site Berlin, German Center for Child and Adolescent Health (Deutsches Zentrum für Kinder- und Jugendgesundheit)
  24. 24Dr von Hauner’s Children’s Hospital, Ludwig-Maximilians-Universität München Munich
  25. 25Department of Pediatrics, Helios Klinikum
  26. 26Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust
  27. 27HMU Health and Medical University, Campus Düsseldorf/Krefeld
  28. 28Université Paris Cité, Institut Imagine, Laboratory of human genetics of infectious diseases, Necker branch, INSERM UMR 1163
  29. 29Department of Paediatric Neurology, Evelina London Children’s Hospital
  30. 30Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine, King’s College London
  31. 31Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne
  32. 32Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne
Read full textPDFDOICite

Abstract

Background: The leukemia inhibitory factor receptor (LIFR) is a key signaling receptor within the IL-6 cytokine-family, and its integrity is essential for STAT3 and ERK activation in developmental and immune pathways. Recessive, predominantly truncating variants in LIFR cause Stüve-Wiedemann syndrome (SWS), historically a neonatal-lethal skeletal dysplasia. As more individuals survive beyond infancy, the clinical spectrum and its biological basis remain incompletely defined.

Methods: We describe the clinical heterogeneity with considerable survival beyond infancy and phenotypic expansions in neurodevelopment and immune dysregulation and determine how missense variants alter cytokine and receptor trafficking. To define the expanded disease spectrum and underlying mechanisms, we assembled an international cohort of 22 previously unreported individuals with biallelic LIFR variants, combined with functional characterization of missense alleles using cellular receptor abundance and STAT/ERK signaling assays, and proteomic profiling of patient-derived bronchoalveolar lavage (BAL) cells.

Results: We identified a markedly expanded phenotype among survivors beyond infancy, including neurodevelopmental disorders, allergy, and hyperinflammatory courses, including COVID-19–associated multisystem inflammatory syndrome in children (MIS-C). In cellular assays, the hypomorphic missense variant p.Cys270Gly showed reduced cell-surface LIF-receptor abundance, STAT/ERK phosphorylation and cellular proliferation upon LIF stimulation. Analysis of additional missense variants revealed functional domain-specific effects: N-terminal extracellular variants retained partial activity, whereas C-terminal cytoplasmic variants showed near-complete loss-of-function. Patient bronchoalveolar-cell proteomics identified dysregulations in endolysosomal recycling of defective LIF-receptor.

Discussion: Our cohort’s findings may position LIFR deficiency as a survivable multisystem disorder with relevant neurological and autoimmune-inflammatory vulnerability. Variant-level functional stratification and proteomic signatures provide a coherent biological framework to support risk assessment and long-term clinical management in affected individuals.

Related

  1. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families
    Mehdi Benkirane, Cecilia Marelli, Claire Guissart +82
    Genetics in MedicinePeer-reviewedLicence not stated28 citedGenetics & genomicsHAL
  2. Re-Analysis on GRCh38 with the MANE Select Transcript Resolves Previously Undetected Biallelic ODAD4 Variants in Primary Ciliary Dyskinesia
    Petra Pennekamp, Marina Praprotnik, Bernd Dworniczak +2
    CellsPeer-reviewedCC BY 4.0Full textGenetics & genomicsCrossrefEurope PMC
  3. Familial dystonic Choreoathetosis associated with Biallelic ATM variants
    Marek Godava, Lenka Satke, Pavel Otruba +4
    Frontiers in NeurologyPeer-reviewedCC BY 4.0Full textNeuroscienceCrossref
  4. Genetic and Clinical Characterization of Early-Onset High Myopia With or Without Cataract Due to Biallelic P3H2 Variants
    Xinyu Su, Yi Jiang, Yuxi Zheng +4
    Investigative Ophthalmology & Visual SciencePeer-reviewedCC BY-NC-ND 4.0Full textGenetics & genomicsPMC
  5. Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability
    Gorka Fernández-Eulate, Romain Duval, Marina Konyukh +32
    Annals of NeurologyPeer-reviewedCC BY-NC-NDFull textNeuroscienceHAL

Cite

BibTeXRIS
BibTeX
@article{schmidt2026hypomorphic,
  title = {{Hypomorphic biallelic LIFR variants define a multisystem disorder with survival beyond infancy and hyperinflammatory vulnerability}},
  author = {Madeleine Schmidt and Puyan Rafii and Aisha AlShamsi and Giovanni Zifarelli and Maxi Leona Wiese and Joachim David Steiner and Sarah Kreuz and Robert Walter Körner and Clara Velmans and Christian Netzer and Oliver Semler and Majid Alfadhel and Hiba Abu Khalil and Ezgi Susam and Sujatha Jagadeesh and Beena Suresh and Nicolai Kohlschmidt and Philip M. Boone and Sheela Nampoothiri and Radhakrishnan Periyasamy and Katta M. Girisha and Andreas Hahn and Adela Chirita-Emandi and Raphael Hirtz and Kai O. Hensel and Peter Bauer and Konstantin L. Makridis and Angela M. Kaindl and Ilja Dubinski and Jürgen-Christoph von Kleist-Retzow and Gregor Dückers and Reem Elfeky and Maaike Kusters and Tim Niehues and Vivien Béziat and Heinz Jungbluth and Adam Antebi and Jürgen Scheller and Hormos S. Dafsari},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1927542},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1927542/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Hypomorphic biallelic LIFR variants define a multisystem disorder with survival beyond infancy and hyperinflammatory vulnerability
AU  - Madeleine Schmidt
AU  - Puyan Rafii
AU  - Aisha AlShamsi
AU  - Giovanni Zifarelli
AU  - Maxi Leona Wiese
AU  - Joachim David Steiner
AU  - Sarah Kreuz
AU  - Robert Walter Körner
AU  - Clara Velmans
AU  - Christian Netzer
AU  - Oliver Semler
AU  - Majid Alfadhel
AU  - Hiba Abu Khalil
AU  - Ezgi Susam
AU  - Sujatha Jagadeesh
AU  - Beena Suresh
AU  - Nicolai Kohlschmidt
AU  - Philip M. Boone
AU  - Sheela Nampoothiri
AU  - Radhakrishnan Periyasamy
AU  - Katta M. Girisha
AU  - Andreas Hahn
AU  - Adela Chirita-Emandi
AU  - Raphael Hirtz
AU  - Kai O. Hensel
AU  - Peter Bauer
AU  - Konstantin L. Makridis
AU  - Angela M. Kaindl
AU  - Ilja Dubinski
AU  - Jürgen-Christoph von Kleist-Retzow
AU  - Gregor Dückers
AU  - Reem Elfeky
AU  - Maaike Kusters
AU  - Tim Niehues
AU  - Vivien Béziat
AU  - Heinz Jungbluth
AU  - Adam Antebi
AU  - Jürgen Scheller
AU  - Hormos S. Dafsari
PY  - 2026
DA  - 2026/10/19
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1927542
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1927542/full
AB  - Background: The leukemia inhibitory factor receptor (LIFR) is a key signaling receptor within the IL-6 cytokine-family, and its integrity is essential for STAT3 and ERK activation in developmental and immune pathways. Recessive, predominantly truncating variants in LIFR cause Stüve-Wiedemann syndrome (SWS), historically a neonatal-lethal skeletal dysplasia. As more individuals survive beyond infancy, the clinical spectrum and its biological basis remain incompletely defined.  Methods: We describe the clinical heterogeneity with considerable survival beyond infancy and phenotypic expansions in neurodevelopment and immune dysregulation and determine how missense variants alter cytokine and receptor trafficking. To define the expanded disease spectrum and underlying mechanisms, we assembled an international cohort of 22 previously unreported individuals with biallelic LIFR variants, combined with functional characterization of missense alleles using cellular receptor abundance and STAT/ERK signaling assays, and proteomic profiling of patient-derived bronchoalveolar lavage (BAL) cells.  Results: We identified a markedly expanded phenotype among survivors beyond infancy, including neurodevelopmental disorders, allergy, and hyperinflammatory courses, including COVID-19–associated multisystem inflammatory syndrome in children (MIS-C). In cellular assays, the hypomorphic missense variant p.Cys270Gly showed reduced cell-surface LIF-receptor abundance, STAT/ERK phosphorylation and cellular proliferation upon LIF stimulation. Analysis of additional missense variants revealed functional domain-specific effects: N-terminal extracellular variants retained partial activity, whereas C-terminal cytoplasmic variants showed near-complete loss-of-function. Patient bronchoalveolar-cell proteomics identified dysregulations in endolysosomal recycling of defective LIF-receptor.  Discussion: Our cohort’s findings may position LIFR deficiency as a survivable multisystem disorder with relevant neurological and autoimmune-inflammatory vulnerability. Variant-level functional stratification and proteomic signatures provide a coherent biological framework to support risk assessment and long-term clinical management in affected individuals.
SN  - 1664-3224
ER  -