Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we used the ACTB-Cre gene to activate a conditional Akt1 p.(E17K) allele in the mouse. No offspring that was heterozygous for both Cre and the conditional allele (βA-Akt1^WT/flx) was viable. Fewer than expected numbers of βA-Akt1^WT/flx embryos were seen beginning at E11.5, but a few survived until E17.5. The phenotype ranged from mild to severe, but generally βA-Akt1^WT/flx embryos had fewer visible blood vessels and more hemorrhages than their wild-type littermates, which was suggestive of a vascular abnormality. Examination of E13.5 limb skin showed a primitive capillary network with increased branching complexity and abnormal patterning compared with wild-type skin. By E15.5, wild-type skin had undergone angiogenesis and formed a hierarchical network of remodeled vessels, whereas in βA-Akt1^WT/flx embryos, the capillary network failed to remodel. Mural cell coverage of the blood vessels was also reduced in βA-Akt1^WT/flx skin compared with that of wild type. Restricting expression of Akt1^E17K to endothelial, cardiac or smooth muscle cells resulted in viable offspring and remodeled vasculature and did not recapitulate the βA-Akt1^WT/flx phenotype. We conclude that ubiquitous expression of Akt1^E17K suppresses remodeling and inhibits the formation of a normal skin vasculature. We postulate that this failure prevents proper circulation necessary to support the growing embryo and that it is the result of interactions of multiple cell types with increased AKT signaling.

中文翻译：

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Akt1 p.(E17K) 的普遍表达导致小鼠血管缺陷和胚胎致死

Proteus 综合征是一种进行性过度生长疾病，由AKT1 c.49G > A, p.(E17K) 激活变体的镶嵌表达引起的血管畸形，如果普遍表达，预计会导致致死。为了验证该假设，我们使用ACTB-Cre基因激活小鼠中的条件Akt1 p.(E17K) 等位基因。对于Cre和条件等位基因 ( βA-Akt1 ^WT/flx ) 而言，没有杂合子是可行的。从 E11.5 开始观察到的βA-Akt1 ^WT/flx胚胎数量少于预期，但少数存活到 E17.5。表型范围从轻度到重度，但通常为βA-Akt1 ^WT/flx与野生型同窝仔相比，胚胎的可见血管更少，出血更多，这表明存在血管异常。与野生型皮肤相比，E13.5 肢体皮肤的检查显示原始毛细血管网络具有增加的分支复杂性和异常图案。到 E15.5，野生型皮肤经历了血管生成并形成了重构血管的分层网络，而在βA-Akt1 ^WT/flx胚胎中，毛细血管网络未能重构。与野生型相比，βA-Akt1 ^WT/flx皮肤的血管壁细胞覆盖率也降低。限制Akt1 ^{E17K 的}表达内皮细胞、心肌细胞或平滑肌细胞产生可存活的后代和重塑的脉管系统，并且没有重现βA-Akt1 ^WT/flx表型。我们得出结论，Akt1 ^{E17K 的}普遍表达抑制重塑并抑制正常皮肤脉管系统的形成。我们假设这种失败阻止了支持生长胚胎所需的适当循环，这是多种细胞类型与增加的 AKT 信号相互作用的结果。