Alternative titles; symbols
HGNC Approved Gene Symbol: RASA2
Cytogenetic location: 3q23 Genomic coordinates (GRCh38): 3:141,487,027-141,615,344 (from NCBI)
Maekawa et al. (1994) isolated a mammalian GTPase-activating protein of RAS from rat (GAP1M) that shows sequence similarity to the suppressor of RAS (see 190020) function in Drosophila, known as Gap1 (Gaul et al., 1992). Expression was relatively high in brain, placenta, and kidney but lower in other tissues. A recombinantly expressed protein containing the GAP-related domain was shown to stimulate GTPase activity of RAS.
Li et al. (1996) isolated the human homolog of rat GAP1M from a brain cDNA library. The deduced 853-amino acid protein is 89.4% identical to the rat protein.
Using a panel of somatic cell hybrid DNAs, Li et al. (1996) mapped the human GAP1M gene to chromosome 3. By fluorescence in situ hybridization, they mapped GAP1M to chromosome 3q22-q23.
Somatic Mutation
Arafeh et al. (2015) analyzed 501 melanoma (see 155600) exomes and found that RASA2 was mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation and melanoma cell growth and migration. RASA2 expression was lost in at least 30% of human melanomas analyzed and was associated with reduced patient survival.
Associations Pending Confirmation
Among 27 Noonan syndrome (see 163950) patients who were negative for mutations in known causative genes, Chen et al. (2014) identified 3 who carried missense mutations in RASA2. Two of the patients had changes in the same codon, tyr326; one mutation was tyr326 to cys (Y326C) and the other was tyr326 to asn (Y326N). The third patient carried an arg511-to-cys (R511C) variant. The patient (NS78) with the Y326C mutation also carried a mutation in RIT1 (F82V; 609591.0005) known to cause Noonan syndrome-8 (615355). No parental DNA was available for segregation analysis. Knockdown studies of RASA2 showed that it plays a role in the RAS-ERK pathway, but no functional testing of these variants was reported.
Arafeh, R., Qutob, N., Emmanuel, R., Keren-Paz, A., Madore, J., Elkahloun, A., Wilmott, J. S., Gartner, J. J., Di Pizio, A., Winograd-Katz, S., Sindiri, S., Rotkopf, R., and 16 others. Recurrent inactivating RASA2 mutations in melanoma. Nature Genet. 47: 1408-1410, 2015. [PubMed: 26502337] [Full Text: https://doi.org/10.1038/ng.3427]
Chen, P.-C., Yin, J., Yu, H.-W., Yuan, T., Fernandez, M., Yung, C. K., Trinh, Q. M., Peltekova, V. D., Reid, J. G., Tworog-Dube, E., Morgan, M. B., Muzny, D. M., Stein, L., McPherson, J. D., Roberts, A. E., Gibbs, R. A., Neel, B. G., Kucherlapati, R. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc. Nat. Acad. Sci. 111: 11473-11478, 2014. [PubMed: 25049390] [Full Text: https://doi.org/10.1073/pnas.1324128111]
Gaul, U., Mardon, G., Rubin, G. M. A putative Ras GTPase activating protein acts as a negative regulator of signaling by the Sevenless receptor tyrosine kinase. Cell 68: 1007-1019, 1992. [PubMed: 1547500] [Full Text: https://doi.org/10.1016/0092-8674(92)90073-l]
Li, S., Satoh, H., Watanabe, T., Nakamura, S., Hattori, S. cDNA cloning and chromosomal mapping of a novel human GAP (GAP1M), a GTPase-activating protein of Ras. Genomics 35: 625-627, 1996. [PubMed: 8812506] [Full Text: https://doi.org/10.1006/geno.1996.0412]
Maekawa, M., Li, S., Iwamatsu, A., Morishita, T., Yokota, K., Imai, Y., Kohsaka, S., Nakamura, S., Hattori, S. A novel mammalian Ras GTPase-activating protein which has phospholipid-binding and Btk homology regions. Molec. Cell. Biol. 14: 6879-6885, 1994. [PubMed: 7935405] [Full Text: https://doi.org/10.1128/mcb.14.10.6879-6885.1994]