Blood Vascular Abnormalities in Rasa1R780Q Knockin Mice Implications for the Pathogenesis of Capillary Malformation-Arterio venous Malformation
Blood Vascular Abnormalities in Rasa1R780Q Knockin Mice Implications for the Pathogenesis of Capillary Malformation-Arterio venous Malformation
复制标题
DOI：
10.1016/j.ajpath.2014.08.018
复制
发表时间：
2014-12-01
影响因子：
6
通讯作者：
King, Philip D.
中科院分区：
文献类型：
--
作者：
Lubeck, Beth A.;Lapinski, Philip E.;King, Philip D.
毛细血管畸形动静脉畸形（CM-AVM）是一种常染色体显性遗传性血管病，以CM和快速血流BV病变为特征。RASA 1基因的失活突变是大多数病例中CM-AVM的原因。RASA 1是一种GTP酶激活蛋白，作为Ras小GTP结合蛋白的负调节因子。此外，RASA 1在细胞内信号转导中执行Ras独立功能。尚不清楚CM-AVM是由于RASA 1调节Ras的能力丧失还是RASA 1的Ras独立功能丧失所致。为了解决这个问题，我们产生了Rasa 1敲入小鼠与R780 Q点突变，废除RASA 1催化活性特异性。纯合子Rasa 1（R780 Q/R780 Q）小鼠表现出与Rasa 1基因敲除小鼠相同的严重BV异常，并在妊娠中期死亡。这一发现表明，CM-AVM中BV异常的发生是由于RASA 1控制Ras激活的能力丧失，而不是该分子的Ras独立功能丧失。更重要的是，研究结果表明，抑制Ras信号可能是治疗这种疾病的有效手段。
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.