Garrigue Alexandrine, Kermasson Laëtitia, Susini Sandrine, Fert Ingrid, Mahony Christopher B, Sadek Hanem, Luce Sonia, Chouteau Myriam, Cavazzana Marina, Six Emmanuelle, Le Bousse-Kerdilès Marie-Caroline, Anginot Adrienne, Souraud Jean-Baptiste, Cormier-Daire Valérie, Willems Marjolaine, Sirvent Anne, Russello Jennifer, Callebaut Isabelle, André Isabelle, Bertrand Julien Y, Lagresle-Peyrou Chantal, Revy Patrick
Institut Imagine, Université Paris Cité, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.
INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Équipe Labellisée LIGUE 2023, Paris, France.
J Clin Invest. 2025 Jan 23;135(6):e180981. doi: 10.1172/JCI180981.
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.
抑瘤素M（OSM）是一种细胞因子，具有与OSM受体（OSMR）和白血病抑制因子受体（LIFR）相互作用的独特能力。另一方面，OSMR与IL31RA相互作用形成白细胞介素-31受体。这种复杂的细胞因子和受体网络使得理解OSM的具体功能变得困难。虽然OSMR中的单等位基因功能丧失（LoF）突变是常染色体显性遗传性家族性原发性局限性皮肤淀粉样变性的基础，但迄今为止，人类OSM缺乏的体内后果从未被报道过。在这里，我们从一个近亲家庭中鉴定出3名年轻个体，他们患有遗传性严重骨髓衰竭综合征（IBMFS），其特征为严重贫血、血小板减少和中性粒细胞减少。基因分析显示，与该疾病相关的OSM序列中有一个纯合的1个碱基对插入。结构和功能分析表明，该变体导致移码，用一个新肽取代了OSM的C末端部分，该部分包含与OSMR和LIFR相互作用的FxxK基序。突变型OSM缺乏检测和信号传导表明存在LoF突变。斑马鱼模型分析进一步支持了OSM/OSMR信号在红系祖细胞增殖和中性粒细胞分化中的作用。我们的研究提供了人类OSM缺乏以前未被描述且出乎意料的有限体内后果。
