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

Graphical Abstract. © 2025, Garrigue et al

SUMMARY

Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukaemia 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 localised cutaneous amyloidosis, the in vivo consequences of human OSM deficiency have never been reported so far. Here, the authors identified 3 young individuals from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterised by profound anaemia, 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 signalling of the mutant OSM suggests a LoF mutation. Analysis of zebrafish models further supported the role of the OSM/OSMR signalling in erythroid progenitor proliferation and neutrophil differentiation. Their study provides the previously uncharacterized and unexpectedly limited in vivo consequence of OSM deficiency in humans.

Full article: https://doi.org/10.1172/JCI180981

WHY IS IT IMPORTANT?

This study reveals a new genetic cause of a life-threatening blood disorder. Researchers found that a rare mutation in a gene called oncostatin M (OSM) leads to severe bone marrow failure in affected children. The patients had dangerously low levels of red blood cells, platelets, and neutrophils, which are crucial for oxygen delivery, blood clotting, and infection defence. OSM is a signalling protein that helps regulate how blood cells are made. By studying this rare deficiency in both humans and zebrafish, the team showed that OSM plays a key role in supporting blood cell production in the bone marrow. This discovery not only uncovers a new inherited disease but also improves our understanding of how blood forms, with potential implications for treating other blood disorders in the future.

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