title: Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis.
abstract: Phenotype-driven approaches to gene discovery using inbred mice have been instrumental in identifying genetic determinants of inherited blood dyscrasias. The recessive mutant scat (severe combined anemia and thrombocytopenia) alternates between crisis and remission episodes, indicating an aberrant regulatory feedback mechanism common to erythrocyte and platelet formation. Here, we identify a missense mutation (G125V) in the scat Rasa3 gene, encoding a Ras GTPase activating protein (RasGAP), and elucidate the mechanism producing crisis episodes. The mutation causes mislocalization of RASA3 to the cytosol in scat red cells where it is inactive, leading to increased GTP-bound Ras. Erythropoiesis is severely blocked in scat crisis mice, and ~94% succumb during the second crisis (~30 d of age) from catastrophic hematopoietic failure in the spleen and bone marrow. Megakaryopoiesis is also defective during crisis. Notably, the scat phenotype is recapitulated in zebrafish when rasa3 is silenced. These results highlight a critical, conserved, and nonredundant role for RASA3 in vertebrate hematopoiesis.
authors: Mammalian Genetics, New York Blood Center, New York, NY 10065, USA. mail: Lblanc@NSHS.edu
authors: Lionel
authors: L
authors: Blanc
authors: Steven L
authors: SL
authors: Ciciotte
authors: Babette
authors: B
authors: Gwynn
authors: Gordon J
authors: GJ
authors: Hildick-Smith
authors: Eric L
authors: EL
authors: Pierce
authors: Kathleen A
authors: KA
authors: Soltis
authors: Jeffrey D
authors: JD
authors: Cooney
authors: Barry H
authors: BH
authors: Paw
authors: Luanne L
authors: LL
authors: Peters
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004789:Enzyme Activation / Q000502:physiology; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D034061:Thrombopoiesis / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; C061107:inositol-1,3,4,5-tetrakisphosphate receptor; D020558:GTP Phosphohydrolases