Somatic Loss-of-Function PIK3R1 and Activating Non-hotspot PIK3CA Mutations Associated with Capillary Malformation with Dilated Veins (CMDV)

De Bortoli, Martina; Queisser, Angela; Pham, Van Cuong; Dompmartin, Anne; Helaers, Raphaël; Boutry, Simon; Claus, Cathy; De Roo, An-Katrien; Hammer, Frank; Brouillard, Pascal; Abdelilah-Seyfried, Salim; Boon, Laurence M.; Vikkula, Miikka

doi:10.1016/j.jid.2024.01.033

Cited by 1 publication

(1 citation statement)

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“…These findings underscore the crucial role of this pathway in vascular integrity and homeostasis. A recent study identified somatic LOF mutations in PIK3R1 and GOF mutations in PIK3CA that were associated with a novel vascular malformation termed capillary malformation with dilated veins (CMDV) ( 90 ).…”

Section: Pathological Pi3k Signaling In Vascular Anomaliesmentioning

confidence: 99%

Shear stress and pathophysiological PI3K involvement in vascular malformations

Abdelilah-Seyfried,

Ola

2024

Journal of Clinical Investigation

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Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα ( PIK3CA ). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA -related vascular anomalies, or “PIKopathies,” range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA -related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA ’s role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA ’s role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.

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Section: Pathological Pi3k Signaling In Vascular Anomaliesmentioning

confidence: 99%