Department of Nephrology & Rheumatology, Kunming Children's Hospital, Kunming 650228, Yunnan, China.
Department of Nephrology, First Affiliated Hospital of Kunming Medical University, Yunnan Clinical Medical Research Center of Chronic Kidney Disease, Kunming 650032, Yunnan, China.
Int Immunopharmacol. 2024 Oct 25;140:112755. doi: 10.1016/j.intimp.2024.112755. Epub 2024 Aug 3.
STAT3 gain-of-function syndrome, characterized by early-onset autoimmunity and primary immune regulatory disorder, remains poorly understood in terms of its immunological mechanisms. We employed whole-genome sequencing of familial trios to elucidate the pivotal role of de novo mutations in genetic diseases. We identified 37 high-risk pathogenic loci affecting 23 genes, including a novel STAT3 c.508G>A mutation. We also observed significant down-regulation of pathogenic genes in affected individuals, potentially associated with inflammatory responses regulated by PTPN14 via miR378c. These findings enhance our understanding of the pathogenesis of STAT3 gain-of-function syndrome and suggest potential therapeutic strategies. Notably, combined JAK inhibitors and IL-6R antagonists may offer promising treatment avenues for mitigating the severity of STAT3 gain-of-function syndrome.
STAT3 功能获得综合征的特征是早期发生自身免疫和原发性免疫调节紊乱，但人们对其免疫机制仍知之甚少。我们通过对家族性三胞胎进行全基因组测序，阐明了新生突变在遗传疾病中的关键作用。我们鉴定出了 37 个影响 23 个基因的高危致病性基因座，其中包括一个新的 STAT3 c.508G>A 突变。我们还观察到，在受影响的个体中，致病性基因存在显著下调，这可能与 PTPN14 通过 miR378c 调控的炎症反应有关。这些发现增进了我们对 STAT3 功能获得综合征发病机制的理解，并提示了潜在的治疗策略。值得注意的是，联合 JAK 抑制剂和 IL-6R 拮抗剂可能为减轻 STAT3 功能获得综合征的严重程度提供有前途的治疗途径。
