Somatic loss-of-function PIK3R1 and activating non-hotspot PIK3CA mutations associated with Capillary Malformation with Dilated Veins (CMDV)
(2024) The Journal of Investigative Dermatology — Vol. 144, n° 9, p. 2066-2077 (2024)
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- Authors
De Bortoli, Martina 
Pham, Van Cuong Dompmartin, Anne Boutry, Simon Claus, Cathy
- Abstract
- Common capillary malformations (CMs) are red vascular skin lesions, most commonly associated with somatic activating GNAQ or GNA11 mutations. We focused on CMs lacking such a mutation to identify novel genetic causes. We used targeted next-generation-sequencing on 82 lesions. Bioinformatic analysis allowed the identification of 9 somatic pathogenic variants in PIK3R1 and PIK3CA, encoding for the regulatory and catalytic subunits of the PI3K kinase, respectively. Re-characterization of these lesions unraveled a common phenotype: a pale Capillary Malformation associated with visible Dilated Veins (CMDV). Primary-endothelial cells from two PIK3R1-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 PIK3R1 were further studied using zebrafish embryos. Endothelium-specific expression of PIK3R1 mutants resulted in abnormal development of the posterior capillary-venous plexus. In summary, CMDV emerges as a clinical entity associated with somatic pathogenic variants in PIK3R1 or PIK3CA (non-hotspot). Our findings suggest that the activated AKT signaling can be effectively reversed by PI3K-pathway inhibitors. Additionally, the proposed zebrafish model, holds promise as a valuable tool for future drug screening aimed at developing patient-tailored treatments.
- Affiliations
WEL Research Institute WELBIO department
Citations
De Bortoli, M., Queisser, A., Pham, V. C., Dompmartin, A., Helaers, R., Boutry, S., Claus, C., De Roo, A.-K., Hammer, F., Brouillard, P., Abdelilah-Seyfried, S., Boon, L., & Vikkula, M. (2024). Somatic loss-of-function PIK3R1 and activating non-hotspot PIK3CA mutations associated with Capillary Malformation with Dilated Veins (CMDV). The Journal of Investigative Dermatology, 144(9), 2066-2077. https://doi.org/10.1016/j.jid.2024.01.033 (Original work published 2024)