Common capillary malformations are red vascular skin lesions, most commonly associated with somatic activating or mutations. We focused on capillary malformations lacking such a mutation to identify previously unreported genetic causes. We used targeted next-generation sequencing on 82 lesions. Bioinformatic analysis allowed the identification of 9 somatic pathogenic variants in and , encoding for the regulatory and catalytic subunits of phosphoinositide 3-kinase, respectively. Recharacterization of these lesions unraveled a common phenotype: a pale capillary malformation associated with visible dilated veins. Primary endothelial cells from 2 -mutated lesions were isolated, and PI3k-Akt-mTOR and RAS–RAF–MAPK signaling were assessed by western blot This unveiled an abnormal increase in Akt phosphorylation, effectively reduced by PI3K pathway inhibitors, such as mTOR, Akt, and PIK3CA inhibitors. The effects of mutant were further studied using zebrafish embryos. Endothelium-specific expression of mutants resulted in abnormal development of the posterior capillary–venous plexus. In summary, capillary malformation associated with visible dilated veins emerges as a clinical entity associated with somatic pathogenic variants in or (nonhotspot). Our findings suggest that the activated Akt signaling can be effectively reversed by PI3K pathway inhibitors. In addition, the proposed zebrafish model holds promise as a valuable tool for future drug screening aimed at developing patient-tailored treatments.

中文翻译：

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与扩张静脉毛细血管畸形 (CMDV) 相关的体细胞 PIK3R1 功能丧失和激活非热点 PIK3CA 突变

常见的毛细血管畸形是红色血管皮肤病变，最常见与体细胞激活或突变有关。我们专注于缺乏这种突变的毛细血管畸形，以识别以前未报告的遗传原因。我们对 82 个病变使用了靶向下一代测序。生物信息学分析鉴定了 和 中的 9 个体细胞致病性变异，分别编码磷酸肌醇 3-激酶的调节亚基和催化亚基。对这些病变的重新定性揭示了一个常见的表型：苍白的毛细血管畸形，伴有可见的扩张静脉。分离来自 2 个突变病变的原代内皮细胞，并通过蛋白质印迹评估 PI3k-Akt-mTOR 和 RAS-RAF-MAPK 信号传导这揭示了 Akt 磷酸化的异常增加，可通过 PI3K 途径抑制剂（例如 mTOR、Akt）有效减少和 PIK3CA 抑制剂。使用斑马鱼胚胎进一步研究了突变体的影响。突变体的内皮特异性表达导致后毛细血管-静脉丛的异常发育。总之，与可见扩张静脉相关的毛细血管畸形是与 或 （非热点）体细胞致病性变异相关的临床实体。我们的研究结果表明，PI3K 通路抑制剂可以有效逆转激活的 Akt 信号传导。此外，所提出的斑马鱼模型有望成为未来药物筛选的宝贵工具，旨在开发针对患者的治疗方案。