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

被引：3

作者：

De Bortoli, Martina ^{[1
]}

Queisser, Angela ^{[1
]}

Pham, Van Cuong ^{[2
]}

Dompmartin, Anne ^{[3
]}

Helaers, Raphal ^{[1
]}

Boutry, Simon ^{[1
,4
]}

Claus, Cathy ^{[5
]}

De Roo, An-Katrien ^{[5
,6
,7
]}

Hammer, Frank ^{[8
]}

Brouillard, Pascal ^{[1
]}

Abdelilah-Seyfried, Salim ^{[2
]}

Boon, Laurence M. ^{[1
,5
]}

Vikkula, Miikka ^{[1
,5
,9
]}

机构：

[1] UCLouvain, Duve Inst, Lab Human Mol Genet, Brussels, Belgium

[2] Univ Potsdam, Inst Biochem & Biol, Potsdam, Germany

[3] Univ Caen Basse Normandie, VASCERN VASCA European Reference Ctr, Dept Dermatol, Caen, France

[4] Vrije Univ Brussel, Univ Libre Bruxelles, Interuniv Inst Bioinformat Brussels, Brussels, Belgium

[5] UCLouvain, VASCERN VASCA European Reference Ctr, Div Plast Surg, Clin Univ St Luc,Ctr Vasc Anomalies, Brussels, Belgium

[6] UCLouvain, VASCERN VASCA European Reference Ctr, Clin Univ St Luc, Serv Anatomopathol, Brussels, Belgium

[7] UCLouvain, Inst Expt & Clin Res, Brussels, Belgium

[8] UCLouvain, VASCERN VASCA European Reference Ctr, Dept Med Imaging, Clin Univ St Luc, Brussels, Belgium

[9] WEL Res Inst, WELBIO Dept, Wavre, Belgium

来源：

JOURNAL OF INVESTIGATIVE DERMATOLOGY | 2024年 / 144卷 / 09期

基金：

瑞士国家科学基金会;

关键词：

Endothelial; NGS; PI3K signaling; Somatic; Zebrafish; VENOUS MALFORMATION; OVERGROWTH; P85-ALPHA;

D O I：

10.1016/j.jid.2024.01.033

中图分类号：

R75 [皮肤病学与性病学];

学科分类号：

100206 ;

摘要：

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.

引用

页数：18