Search

Some studies suggest that the inactivation of the Ras-MAPK pathway in trophoblast cells can lead to recurrent abortion, but the molecular mechanism underlying the inactivation of this pathway in trophoblast cells is still unclear. This study aimed to explore the relationship between the mechanism of abnormal activation of RASA1, a regulatory protein of the Ras-MAPK pathway, and unexplained recurrent spontaneous abortion. RT-qPCR was used to detect the transcription levels of RASA1 gene. Immunohistochemistry and Western blot were used to detect the expression levels of the RASA1, Raf and MEK proteins. CCK-8, TUNEL and Transwell assays were used to detect the proliferative, apoptotic, and invasive capacities of HTR-8/SVneo cells. ChIP assays were used to detect the enrichment of H3K27me3 in RASA1 gene promoter. Abortion villi experiments showed that the enrichment of H3K27me3 in the RASA1 gene promoter was reduced, and that both RASA1 gene transcription and RASA1 protein expression were increased. Cell experiments confirmed that RASA1 could decrease the phosphorylated Raf and MEK proteins, inhibit the proliferation and invasion ability, and promote the apoptosis ability of HTR-8/SVneo cells. It was also found that the proliferation and invasion ability as well as the Ras-MAPK pathway activity of HTR-8/SVneo cells were inhibited when treated with histone methyltransferase inhibitor DZNep. RASA1 gene was abnormally activated in unexplained recurrent spontaneous abortion villi due to the decreased enrichment of H3K27me3 in the gene promoter. High expression of RASA1 could inhibit the activity of the Ras-MAPK pathway, and thus inhibit the proliferation and invasion ability of trophoblast cells. more...

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant inherited rare type of vascular malformation encountered in a neonate and first described in 2003. It has been reported in association with heterozygous mutations in the RASA1 gene, which encodes the protein RASp21. In 2010, a German doctor proposed rhodoid nevus as a name for this type of capillary malformation; in ancient Greek, rhodoides means "rose-like" or "rose-colored." Accordingly, CM-AVM could also be called "rhodoid nevus syndrome." We report this case as its very challenging diagnosis with its further differentials and its association with thrombocytopenia. more...

Background: The prevalence of capillary malformations, also known as port-wine stains (PWS), is 0.3%. Familial segregation can occur. The capillary malformation–arteriovenous malformation (CM-AVM) phenotype is caused by mutations in the RASA1 gene. In PWS familial cases, the inheritance is considered to be autosomal dominant with variable penetrance. Objective: Investigation of the heredity of PWS among patients who attended the vascular anomaly section at the Department of Dermatology in Malmoe, Southern Sweden, between 1993 and 2004 and to study the involvement of the RASA1 gene in patients with a positive family history of PWS. Subjects and methods: A total of 254 patients were examined and given a questionnaire regarding family history of PWS. The first group of 175 patients (109 females and 66 males) reported a negative family history. The other group of 65 patients (46 females and 19 males) reported a positive family history (50% parents or brothers and sisters). Results: The heredity of PWS was 27% (65/240). Twenty-one patients with a positive family history and relatives had no CM-AVM phenotype for mutations in the RASA1 gene. Conclusion: PWS may have a stronger heredity component than it was reported earlier and inheritance should be considered when counseling a patient. RASA1 mutations do not explain the PWS in our patients. more...

Capillary malformation–arteriovenous malformation (CM–AVM) is a newly recognized clinical entity caused by mutation of the RASA1 gene, which encodes p120-RasGAP. Here we describe, for the first time, a patient with CM–AVM presenting during the late stages of pregnancy with pulmonary “capillary level” microvascular shunt, worsening cutaneous capillary malformations, and gross fluid overload. Sequencing revealed a novel mutation of the RASA1 gene involving a frameshift mutation in the RASGAP domain of RASA1. This report extends our current genetic and clinical understanding of CM–AVM. © 2013 Wiley Periodicals, Inc. more...

Capillary malformation-arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) disorder that is caused by inherited inactivating mutations of the RASA1 gene, which encodes p120 RasGAP (RASA1), a negative regulator of the Ras small GTP-binding protein. How RASA1 mutations lead to the LV leakage defects that occur in CM-AVM is not understood. Here, we report that disruption of the Rasa1 gene in adult mice resulted in loss of LV endothelial cells (LECs) specifically from the leaflets of intraluminal valves in collecting LVs. As a result, valves were unable to prevent fluid backflow and the vessels were ineffective pumps. Furthermore, disruption of Rasa1 in midgestation resulted in LEC apoptosis in developing LV valves and consequently failed LV valvulogenesis. Similar phenotypes were observed in induced RASA1-deficient adult mice and embryos expressing a catalytically inactive RASA1R780Q mutation. Thus, RASA1 catalytic activity is essential for the function and development of LV valves. These data provide a partial explanation for LV leakage defects and potentially other LV abnormalities observed in CM-AVM. more...

Melanoma shows frequent Ras-Raf-MAPK pathway activation via frequent mutations in NRAS and BRAF. Novel mutations in other components of this pathway such as MEK1, MEK2, MAP3K5, and MAP3K9 have been reported recently by high-throughput sequencing efforts. In addition, NF1 (neurofibromatosis type 1), one of the Ras GTPase activating proteins (RasGAPs), has been shown to be mutated or suppressed in melanoma. However, importance of other RasGAPs has not been addressed in melanoma. To obtain a comprehensive view of melanoma genomes, we conducted whole genome sequencing (WGS) of 15 metastatic melanomas and matched normal PBMC genomes from 13 melanoma patients. All melanoma genomes from these 13 patients contained at least one mutation in genes of Ras-Raf-MAPK pathway (MAPK1, MAP3K1, MAP4K2, MAP3K14, NRAS, and BRAF). Our whole genome analyses also identified two novel somatic missense mutations (p.Tyr472His and p.Leu481Phe) in or around the PH domain in RASA1 gene. RASA1 (RAS p21 protein activator (GTPase activating protein) 1, also called as p120RasGAP) is a GTPase activation protein that negatively regulates Ras by catalyzing the hydrolysis of active Ras-GTP to inactive Ras-GDP. In this study, we addressed possible roles of RASA1 in melanoma tumorigenesis. To determine RASA1 level in melanocytic lesions, immunohistochemical analysis of RASA1 on human melanoma tissue microarray (TMA) containing nevi (n=34), primary melanomas (n=63), lymph node metastasis (n=35), and distal metastasis (n=29) was performed. This analysis has shown the inverse correlation of RASA1 expression to melanoma progression. Functionally, ectopic expression of RASA1 mutant increased soft-agar colony formation and tumor growth while that of wild-type RASA1 decreased. shRNA-mediated knock down of RASA1 promoted soft-agar colony formation and invasion of melanocytes and melanoma cells with BRAF mutation as a consequence of the elevated Ras activity. Here, we established the functional significance of novel somatic missense mutations in RASA1 identified in our WGS study. Collectively, these data implicated that RASA1 inactivation by loss of expression and/or mutation may promote melanoma tumorigenesis. Citation Format: Hyeran Sung, Li Ding, Krishna L. Kanchi, Jane L. Messina, Vernon K. Sondak, Mulé J. James, Richard K. Wilson, Jeffrey S. Weber, Minjung Kim. RASA1 alteration promotes melanoma tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 442. doi:10.1158/1538-7445.AM2014-442 more...

To the Editor: The identification of underlying causal genes in familial forms of cerebrovascular malformations allows the dissection of an increasing number of these disorders at the molecular level. In recent years, mutations in CCM1/KRIT1 , CCM2/MGC4607 , and CCM3/PDCD10 have been found to cause autosomal dominantly inherited cerebral cavernous malformations (CCM1, CCM2, and CCM3). Clinical penetrance appears to differ between the 3 CCM subtypes, but larger clinical studies are required to confirm this observation. A subset of patients with cerebral arteriovenous malformations also shows cutaneous capillary malformations attributable to mutations in the RASA1 gene or is affected by hereditary hemorrhagic telangiectasias (HHT) resulting from mutations in the endoglin gene ( ENG , HHT1), the activin receptor-like kinase1 gene … more...