RASA1: variable phenotype with capillary and arteriovenous malformations.

Abstract

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.

• Authors: Laurence M Boon, John B Mulliken, Miikka Vikkula
• Journal: Current opinion in genetics & development (Curr Opin Genet Dev) Vol. 15 Issue 3 Pg. 265-9 (Jun 2005) ISSN: 0959-437X [Print] England
• PMID: 15917201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• ras GTPase-Activating Proteins

Topics

• Animals
• Arteriovenous Malformations (genetics, metabolism, pathology)
• Capillaries (abnormalities, metabolism, pathology)
• Humans
• Mutation (genetics)
• Phenotype
• ras GTPase-Activating Proteins (classification, genetics, metabolism)