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Publication : Somatic PIK3CA mutations as a driver of sporadic venous malformations.

First Author  Castel P Year  2016
Journal  Sci Transl Med Volume  8
Issue  332 Pages  332ra42
PubMed ID  27030594 Mgi Jnum  J:246143
Mgi Id  MGI:5924264 Doi  10.1126/scitranslmed.aaf1164
Citation  Castel P, et al. (2016) Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med 8(332):332ra42
abstractText  Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limayeet al, 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kalpha administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.
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