RASA1: variable phenotype with capillary and arteriovenous malformations.
Capillary malformation-arteriovenous malformation (CM-AVM) is a newly discovered hereditary disorder. Its defining features are atypical cutaneous multifocal capillary malformations often in association with high-flow lesions: cutaneous, subcutaneous, intramuscular, intraosseous and cerebral arteriovenous malformations and arteriovenous fistulas. Some patients have Parkes Weber syndrome - a large congenital cutaneous vascular stain in an extremity, with bony and soft tissue hypertrophy and microscopic arteriovenous shunting. In the past, arteriovenous malformations and arteriovenous fistulas had been considered non-hereditary. A classical genetic approach was used to identify the locus. Candidate gene screening pinpointed mutations in RASA1 (p120-RASGAP) - a RasGTPase. RASA1 reverts active GTP-bound Ras into inactive GDP-bound form. Murine Rasa1 knockout and tetraploid-aggregated embryos with RNA interference exhibited abnormal vascular development. Lack of RASA1 activity caused inhibition of cell motility, possibly through p190-RhoGAP. Thus, RASA1 defects probably cause abnormal angiogenic remodeling of the primary capillary plexus that cannot be compensated for by other RasGAPs: RASA2, RASAL and NF1. Signaling pathways involving RASA1 might offer novel targets for treatment of high-flow vascular anomalies.
Boon
Laurence M
LM
Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology and University of Louvain Medical School, Brussels, Belgium.
Mulliken
John B
JB
Vikkula
Miikka
M
D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002196:Capillaries / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020703:ras GTPase-Activating Proteins / Q000145:classification / Q000235:genetics* / Q000378:metabolism*
D020703:ras GTPase-Activating Proteins