Centre for Endocrinology, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London, UK.
Gastroenterology Department, Great Ormond Street Hospital, London, UK.
Nat Commun. 2024 Sep 28;15(1):8420. doi: 10.1038/s41467-024-52587-w.
Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease.
出生后生长失败通常归因于生长激素作用失调，但存在明显的遗传和表型异质性。我们报告了来自三个家庭的五名患者，他们表现为身材矮小、免疫功能障碍、特应性皮炎和胃肠道病理，与 QSOX2 的隐性变异有关。QSOX2 编码一种与二硫键异构酶和氧化还原酶活性相关的核膜蛋白。尽管生长激素诱导的 STAT5B 磷酸化增强，但 QSOX2 的缺失会破坏生长激素介导的 STAT5B 核易位。此外，患者来源的真皮成纤维细胞表现出生长激素诱导的线粒体病和线粒体膜电位降低。位于核膜上的 QSOX2 作为调节磷酸化-STAT5B 稳定和易位的守门员。总的来说，QSOX2 缺乏通过损害生长激素-STAT5B 下游活性和线粒体动力学来调节人类生长，这导致多系统功能障碍。此外，我们的工作表明，治疗性重组胰岛素样生长因子-1可能绕过由病理性 QSOX2 变异引起的生长激素-STAT5B 失调，并可能缓解特定器官的疾病。
