title: Blood vascular abnormalities in Rasa1(R780Q) knockin mice: implications for the pathogenesis of capillary malformation-arteriovenous malformation.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Lubeck
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Lapinski
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bauler
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Oliver
authors.affiliation: Biomedical Research Core Facility Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Hughes
authors.affiliation: Biomedical Research Core Facility Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan; Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Saunders
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan. Electronic address: kingp@umich.edu.
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
mesh_terms: D000483:Alleles; D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics*; D001808:Blood Vessels / Q000002:abnormalities*; D002196:Capillaries / Q000002:abnormalities*; D002384:Catalysis; D003433:Crosses, Genetic; D004252:DNA Mutational Analysis; D055879:Gene Knock-In Techniques; D006720:Homozygote; D007150:Immunohistochemistry; D007438:Introns; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D017354:Point Mutation; D019339:Port-Wine Stain / Q000235:genetics*; D015398:Signal Transduction; D020729:p120 GTPase Activating Protein / Q000235:genetics*
chemical_list: C581321:RASA1 protein, mouse; D020729:p120 GTPase Activating Protein