[HTML][HTML] Blood vascular abnormalities in Rasa1R780Q knockin mice: Implications for the pathogenesis of capillary malformation–arteriovenous malformation

BA Lubeck, PE Lapinski, TJ Bauler, JA Oliver… - The American Journal of …, 2014 - Elsevier
BA Lubeck, PE Lapinski, TJ Bauler, JA Oliver, ED Hughes, TL Saunders, PD King
The American Journal of Pathology, 2014Elsevier
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 …
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 Rasa1R780Q/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.
Elsevier