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.

中文翻译：

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人类抑瘤素 M 缺乏症是遗传性严重骨髓衰竭综合征的基础。


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。这种错综复杂的细胞因子和受体网络使得很难理解 OSM 的具体功能。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原发性局限性皮肤淀粉样变性的基础，但迄今为止从未报道过人类 OSM 缺陷的体内后果。在这里，我们确定了来自一个近亲家庭的三名年轻人，他们表现为遗传性严重骨髓衰竭综合征 （IBMFS），其特征是严重贫血、血小板减少症和中性粒细胞减少症。遗传分析显示，与疾病相关的 OSM 序列中存在纯合子 1 碱基对插入。结构和功能分析表明，这种变体导致移码，用新肽取代了 OSM 的 C 端部分，该部分包含与 OSMR 和 LIFR 相互作用的 FxxK 基序。缺乏突变 OSM 的检测和信号转导表明 LoF 突变。斑马鱼模型的分析进一步支持 OSM/OSMR 信号转导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 缺陷以前未表征且出乎意料地有限的体内后果。