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

Autor:	De Bortoli M; Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium., Queisser A; Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium., Pham VC; Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany., Dompmartin A; Department of Dermatology, VASCERN VASCA European Reference Center, Université de Caen Basse Normandie, Caen, France., Helaers R; Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium., Boutry S; Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium., Claus C; Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Center, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium., De Roo AK; Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Center, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium; Service d'anatomopathologie, VASCERN VASCA European Reference Center, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium; Institute of Experimental and Clinical Research, UCLouvain, Brussels, Belgium., Hammer F; Department of Medical Imaging, VASCERN VASCA European Reference Center, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium., Brouillard P; Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium., Abdelilah-Seyfried S; Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany., Boon LM; Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium; Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Center, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium., Vikkula M; Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium; Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Center, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium; WELBIO Department, WEL Research Institute, Wavre, Belgium. Electronic address: miikka.vikkula@uclouvain.be.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2024 Sep; Vol. 144 (9), pp. 2066-2077.e6. Date of Electronic Publication: 2024 Feb 29.
DOI:	10.1016/j.jid.2024.01.033
Abstrakt:	Common capillary malformations are red vascular skin lesions, most commonly associated with somatic activating GNAQ or GNA11 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 PIK3R1 and PIK3CA, 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 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, capillary malformation associated with visible dilated veins emerges as a clinical entity associated with somatic pathogenic variants in PIK3R1 or PIK3CA (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. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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