Human oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome

Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukemia inhibitory factor receptor (LIFR). On the other hand, OSMR interacts with IL31RA to form the interleukin-31 receptor. This intricate network of cytokines and receptors makes it difficult to understand the specific function of OSM. While monoallelic loss-of-function (LoF) mutations in OSMR underlie autosomal dominant familial primary localized cutaneous amyloidosis, the in vivo consequences of human OSM deficiency have never been reported so far. Here, we identified 3 young individuals from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Genetic analysis revealed a homozygous 1 base-pair insertion in the sequence of OSM associated with the disease. Structural and functional analyses showed that this variant causes a frameshift that replaces the C-terminal portion of OSM, which contains the FxxK motif that interacts with both OSMR and LIFR, with a neopeptide. The lack of detection and signaling of the mutant OSM suggests a LoF mutation. Analysis of zebrafish models further supported the role of the OSM/OSMR signaling in erythroid progenitor proliferation and neutrophil differentiation. Our study provides the previously uncharacterized and unexpectedly limited in vivo consequence of OSM deficiency in humans.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-01-23
DOI
https://doi.org/10.1172/jci180981
Citations
6
Primary Topic
Cytokine Signaling Pathways and Interactions
Type
article
Field-Weighted Citation Impact
6.27

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article

Human oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome

Anne Sîrvent, Valérie Cormier‐Daire, Chantal Lagresle‐Peyrou, Myriam Chouteau et al.
6 citations
Journal of Clinical Investigation
Cytokine Signaling Pathways and Interactions
6.27
article

Human oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome

Anne Sîrvent, Valérie Cormier‐Daire, Chantal Lagresle‐Peyrou, Myriam Chouteau, Jennifer Russello, Marina Cavazzana, Sandrine Susini, Hanem Sadek, Julien Bertrand, Patrick Revy, Ingrid Fert, Christopher B. Mahony, Marjolaine Willems, Adrienne Anginot, Emmanuelle Six, Sonia Luce, Isabelle Callebaut, Alexandrine Garrigue, Marie‐Caroline Le Bousse‐Kerdilès, Isabelle André‐Schmutz, Laëtitia Kermasson, Jean-Baptiste Souraud
article en
6 citations

Abstract

Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukemia inhibitory factor receptor (LIFR). On the other hand, OSMR interacts with IL31RA to form the interleukin-31 receptor. This intricate network of cytokines and receptors makes it difficult to understand the specific function of OSM. While monoallelic loss-of-function (LoF) mutations in OSMR underlie autosomal dominant familial primary localized cutaneous amyloidosis, the in vivo consequences of human OSM deficiency have never been reported so far. Here, we identified 3 young individuals from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Genetic analysis revealed a homozygous 1 base-pair insertion in the sequence of OSM associated with the disease. Structural and functional analyses showed that this variant causes a frameshift that replaces the C-terminal portion of OSM, which contains the FxxK motif that interacts with both OSMR and LIFR, with a neopeptide. The lack of detection and signaling of the mutant OSM suggests a LoF mutation. Analysis of zebrafish models further supported the role of the OSM/OSMR signaling in erythroid progenitor proliferation and neutrophil differentiation. Our study provides the previously uncharacterized and unexpectedly limited in vivo consequence of OSM deficiency in humans.

Journal of Clinical InvestigationVol. 135(6)
University of Geneva (CH), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), Sorbonne Université (FR), Centre Hospitalier Universitaire de Montpellier (FR), Laboratoire de Minéralogie & Cosmochimie du Muséum (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpitaux Universitaires Paris-Ouest (FR), Muséum national d'Histoire naturelle (FR), Hôpital d'Instruction des Armées Bégin (FR), Dynamique du noyau (FR), Institut de minéralogie, de physique des matériaux et de cosmochimie (FR), Hôpital Paul-Brousse (FR), Institut des Maladies Génétiques Imagine (FR)
Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Université de Paris
Good health and well-being
Openalex Percentile: Top 4%
Cytokine Signaling Pathways and Interactions
6.27
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