期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 97, 期 6, 页码 914-921出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2015.11.011
关键词
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资金
- Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) program [IAP P7/43-BeMGI]
- National Institutes of Health [P01 AR048564]
- Fonds de la Recherche Scientifique (FRS-FNRS) [T.0026.14]
- Academy of Finland [136880]
- Academy of Finland (Centre of Excellence Program)
- la Communaute Francaise de Wallonie-Bruxelles
- la Lotterie Nationale, Belgium
Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110 alpha subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110 alpha-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects.
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