The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann–like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

中文翻译：

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GP130 细胞因子受体信号传导缺失会导致延长 Stüve-Wiedemann 综合征

IL6ST 基因编码 GP130，它是由 10 种细胞因子组成的 IL-6 细胞因子家族的常见信号转导器。先前的研究已经确定了保留 LIF 信号传导的细胞因子选择性 IL6ST 缺陷。我们描述了三个不相关的家庭，其中至少有 5 名受影响的个体，他们出现致命的 Stüve-Wiedemann 样综合征，其特征是骨骼发育不良和新生儿肺功能障碍，并伴有先天性血小板减少症、湿疹样皮炎、肾脏异常和急性期反应缺陷等其他特征。我们鉴定了 IL6ST 中重要的功能丧失变异（纯合无义变异和具有外显子跳跃的纯合内含子剪接变异）。功能测试显示细胞对 GP130 依赖性细胞因子缺乏反应，包括 IL-6、IL-11、IL-27、制瘤素 M (OSM) 和白血病抑制因子 (LIF)。通过慢病毒转导在患者来源的细胞中对 GP130 进行基因重建，逆转了信号传导缺陷。这项研究发现了一种新的遗传综合征，该综合征是由人类 GP130 依赖性细胞因子全家族信号完全缺失引起的，并强调了 LIF 信号通路在产前和围产期发育中的重要性。