RASA1: Variable phenotype with capillary and arteriovenous malformations

Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology and University of Louvain Medical School, Brussels, Belgium.
Current Opinion in Genetics & Development (Impact Factor: 7.57). 07/2005; 15(3):265-9. DOI: 10.1016/j.gde.2005.03.004
Source: PubMed

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.

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Available from: Miikka Vikkula, May 30, 2014
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    • "Transgenic mouse embryos created from RNAi-mediated RASA1 knockdown in ES cells demonstrated that the severity of vascular defects correlated with the level of residual RasGAP expression, and mosaic embryos develop localized defects [10]. Consistent with these mouse studies, mutations in the RASA1 gene have been linked with familial capillary venous malformation syndromes which can present with a wide range of phenotypes, most commonly that known as a “port wine stain” [11], [12], [13], [14], [15]. Recent proteomic analysis of these skin lesions showed consistent decreased expression of RasGAP compared to surrounding normal tissue [16]. "
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    ABSTRACT: KRAS is mutated in ∼40% of colorectal cancer (CRC), and there are limited effective treatments for advanced KRAS mutant CRC. Therefore, it is crucial that downstream mediators of oncogenic KRAS continue to be studied. We identified p190RhoGAP as being phosphorylated in the DLD1 CRC cell line, which expresses a heterozygous KRAS G13D allele, and not in DKO4 in which the mutant allele has been deleted by somatic recombination. We found that a ubiquitous binding partner of p190RhoGAP, p120RasGAP (RasGAP), is expressed in much lower levels in DKO4 cells compared to DLD1, and this expression is regulated by KRAS. Rescue of RasGAP expression in DKO4 rescued Rho pathway activation and partially rescued tumorigenicity in DKO4 cells, indicating that the combination of mutant KRAS and RasGAP expression is crucial to these phenotypes. We conclude that RasGAP is an important effector of mutant KRAS in CRC.
    PLoS ONE 01/2014; 9(1):e86103. DOI:10.1371/journal.pone.0086103 · 3.23 Impact Factor
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    • "RAS p21 GTPase activating protein 1 (RASA1) participates in the control of cellular proliferation and differentiation by enhancing the weak intrinsic GTPase activity of RAS proteins, thus producing the inactive GDP-bound form of RAS (11). A number of studies have shown that the dysregulation of RASA1 has an oncogenic effect in multiple types of cancer, including colorectal, liver and breast cancer, as well as promyelocytic leukemia (12–16). "
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    ABSTRACT: MicroRNAs (miRNAs) are involved in the pathogenesis of intrahepatic cholangiocarcinoma (ICC). However, the role of microRNA-31 (miR-31) in ICC has yet to be elucidated. In this study, we demonstrated that the expression of miR-31 was significantly upregulated in ICC tissues and the human ICC cell line HCCC-9810, when compared with that in normal adjacent tissues. Bioinformatic analysis and a dual-luciferase reporter assay revealed RAS p21 GTPase activating protein 1 (RASA1) to be a direct target of miR-31 in HCCC-9810 cells. Further investigation showed that the protein expression level of RASA1 was significantly decreased in ICC tissues, suggesting an inverse correlation between miR-31 and RASA1 expression during the tumorigenesis of ICC. Moreover, the forced downregulation of miR-31 by its inhibitor in HCCC-9810 cells significantly inhibited cell proliferation and promoted cell apoptosis. However, when the cells were cotransfected with miR-31 inhibitor and RASA1-specific small interfering RNA (siRNA), these changes were attenuated. Further analysis of the molecular mechanism showed that the activity of the RAS-mitogen-activated protein kinase (MAPK) signaling pathway was significantly decreased in miR-31-downregulated HCCC-8910 cells, while cotransfection with miR-31 inhibitor and RASA1-specific siRNA attenuated this effect. These results indicate that the downregulation of RASA1 by miR-31 promoted cellular proliferation and inhibited cellular apoptosis, partially by upregulating the activity of the RAS-MAPK signaling pathway in ICC. In conclusion, the present study revealed important regulatory functions of miR-31 and RASA1 in ICC, indicating that miR-31 and RASA1 may become promising diagnostic and/or therapeutic targets for ICC.
    Experimental and therapeutic medicine 11/2013; 6(5):1265-1270. DOI:10.3892/etm.2013.1311 · 1.27 Impact Factor
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    • "The RASA1 associated autosomal dominant CM-AVM-syndrome is characterized by multiple pink-red, round, or oval CMs mostly localized on the face and limbs increasing in number with age ( fig. 2 ) [Carr et al., 2011]. About 30% of affected individuals have associated AVMs and/or AVFs which are typically located in the head and neck region [Bayrak-Toydemir and Stevenson, 1993–2011; Boon et al., 2005]. These fast-flow vascular anomalies typically arise in the skin, muscle, bone, spine, and brain, and life-threatening complications may include bleeding, congestive heart failure, or neurologic symptoms which seem to occur early in life [Bayrak-Toydemir and Stevenson , 1993–2011]. "
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    ABSTRACT: Disorders related to the autosomal transcription factor MEF2C located in 5q14.3 were first described in 2009 and have since evolved to one of the more common microdeletion syndromes. Mutational screening in a larger cohort revealed heterozygous de novo mutations of MEF2C in about 1% of patients with moderate to severe intellectual disability, and the phenotype is similar in patients with intragenic deletions and multigenic microdeletions. Clinically, MEF2C-related disorders are characterized by severe intellectual disability with absent speech and limited walking abilities, hypotonia, seizures, and a variety of minor brain anomalies. The majority of patients show a similar facial gestalt with broad forehead, flat nasal bridge, hypotonic mouth, and small chin, as well as strabismus, but this phenotype is clinically not well recognized. The course of the disease is generally quite uniform, but patients with point mutations and smaller deletions seem to have a higher chance of walking skills and a lower risk of refractory seizures. Patients in whom the microdeletion also includes the RASA1 gene show features of the respective capillary and arterio-venous malformations and fistula syndrome. The phenotypic overlap with Rett syndrome is explained by a shared pathway and, accordingly, diminished MECP2 and CDKL5 expression is measureable in patients with MEF2C defects. Further research of this pathway may therefore eventually lead to a common therapeutic target.
    Molecular syndromology 04/2012; 2(3-5):164-170. DOI:10.1159/000337496
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