Blood Vascular Abnormalities in Rasa1(R780Q) Knockin Mice Implications for the Pathogenesis of Capillary Malformation-Arterio venous Malformation

作者：Lubeck Beth A; Lapinski Philip E; Bauler Timothy J; Oliver Jennifer A; Hughes Elizabeth D; Saunders Thomas L; King Philip D^*

来源：American Journal Of Pathology, 2014, 184(12): 3163-3169.

DOI：10.1016/j.ajpath.2014.08.018

Capillary malformation arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascular (BV) disorder characterized by CM and fast flow BV lesions. Inactivating mutations of the RASA1 gene are the cause of CM-AVM in most cases. RASA1 is a GTPase-activating protein that acts as a negative regulator of the Ras small GTP-binding protein. In addition, RASA1 performs Ras-independent functions in intracellular signal transduction. Whether CM-AVM results from Loss of an ability of RASA1 to regulate Ras or loss of a Ras-independent function of RASA1 is unknown. To address this, we generated Rasa1 knockin mice with an R780Q point mutation that abrogates RASA1 catalytic activity specifically. Homozygous Rasa1(R780Q/R780Q) mice showed the same severe BV abnormalities as Rasa1-null mice and died midgestation. This finding indicates that BV abnormalities in CM-AVM develop as a result of Loss of an ability of RASA1 to control Ras activation and not loss of a Ras-independent function of this molecule. More important, findings indicate that inhibition of Ras signaling is likely to represent an effective means of therapy for this disease.

• 出版日期2014-12