PUBLICATION
Human Oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome
- Authors
- Garrigue, A., Kermasson, L., Susini, S., Fert, I., Mahony, C.B., Sadek, H., Luce, S., Chouteau, M., Cavazzana, M., Six, E., Le Bousse-Kerdilès, M.C., Anginot, A., Souraud, J.B., Cormier-Daire, V., Willems, M., Sirvent, A., Russello, J., Callebaut, I., André, I., Bertrand, J.Y., Lagresle-Peyrou, C., Revy, P.
- ID
- ZDB-PUB-250124-5
- Date
- 2025
- Source
- The Journal of Clinical Investigation : (Journal)
- Registered Authors
- Bertrand, Julien, Mahony, Christopher
- Keywords
- Bone marrow, Cytokines, Genetics, Hematology, Hematopoietic stem cells
- MeSH Terms
-
- Oncostatin M Receptor beta Subunit/deficiency
- Oncostatin M Receptor beta Subunit/genetics
- Oncostatin M Receptor beta Subunit/metabolism
- Male
- Oncostatin M*/genetics
- Oncostatin M*/metabolism
- Female
- Pedigree
- Frameshift Mutation
- Zebrafish*/genetics
- Bone Marrow Failure Disorders/genetics
- Bone Marrow Failure Disorders/metabolism
- Bone Marrow Failure Disorders/pathology
- Adult
- Animals
- Leukemia Inhibitory Factor Receptor alpha Subunit/deficiency
- Leukemia Inhibitory Factor Receptor alpha Subunit/genetics
- Leukemia Inhibitory Factor Receptor alpha Subunit/metabolism
- Humans
- PubMed
- 39847438 Full text @ Journal of Clin. Invest.
Citation
Garrigue, A., Kermasson, L., Susini, S., Fert, I., Mahony, C.B., Sadek, H., Luce, S., Chouteau, M., Cavazzana, M., Six, E., Le Bousse-Kerdilès, M.C., Anginot, A., Souraud, J.B., Cormier-Daire, V., Willems, M., Sirvent, A., Russello, J., Callebaut, I., André, I., Bertrand, J.Y., Lagresle-Peyrou, C., Revy, P. (2025) Human Oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome. The Journal of Clinical Investigation. :.
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 three 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 one 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping