PUBLICATION
Somatic loss-of-function PIK3R1 and activating non-hotspot PIK3CA mutations associated with Capillary Malformation with Dilated Veins (CMDV)
- Authors
- 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.M., Vikkula, M.
- ID
- ZDB-PUB-240304-6
- Date
- 2024
- Source
- The Journal of investigative dermatology 144(9): 2066-2077.e6 (Journal)
- Registered Authors
- Abdelilah-Seyfried, Salim
- Keywords
- NGS, PI3K signaling, endothelial, somatic, zebrafish
- MeSH Terms
-
- Aged
- Class I Phosphatidylinositol 3-Kinases*/genetics
- Child
- Signal Transduction/genetics
- Middle Aged
- Adult
- Female
- Capillaries*/abnormalities
- Capillaries*/pathology
- Loss of Function Mutation
- Male
- Vascular Malformations*/genetics
- Vascular Malformations*/pathology
- Humans
- High-Throughput Nucleotide Sequencing
- Zebrafish*/genetics
- Animals
- Veins/abnormalities
- Veins/pathology
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Class Ia Phosphatidylinositol 3-Kinase*/genetics
- Adolescent
- PubMed
- 38431221 Full text @ J. Invest. Dermatol.
Citation
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.M., 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.e6.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping