Alternative titles; symbols
HGNC Approved Gene Symbol: RRAS2
Cytogenetic location: 11p15.2 Genomic coordinates (GRCh38) : 11:14,277,920-14,364,506 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.2 | Noonan syndrome 12 | 618624 | Autosomal dominant | 3 |
| Ovarian carcinoma | 3 |
The TC21 oncogene, a member of the RAS superfamily, was initially cloned from a human teratocarcinoma cDNA library by PCR methods using degenerate oligonucleotides corresponding to the conserved region of the RAS genes (Drivas et al., 1990). Chan et al. (1994) found the same oncogene when they generated an expression cDNA library from an ovarian carcinoma (167000) line. They found, furthermore, that a single point mutation (see MOLECULAR GENETICS) was responsible for activation of transforming properties. While the cDNA clone possessed high transforming activity, the ovarian tumor genomic DNA, which contained the mutated TC21 allele, failed to induce transformed foci. Thus, expression cDNA cloning made it possible to identify and isolate a human oncogene that had evaded detection by conventional approaches.
Using X-gal staining and RT-PCR analyses, Larive et al. (2012) showed that Rras2 was expressed from early developmental stages to adulthood in mice. In adult mice, highest expression was in lung and testis, and lowest expression was in tongue, liver, skeletal muscle, and brown adipose.
Gross (2020) mapped the RRAS2 gene to chromosome 11p15.2 based on an alignment of the RRAS2 sequence (GenBank AF493924) with the genomic sequence (GRCh38).
Noonan Syndrome 12
In 9 patients from 6 unrelated families with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygous germline mutations in the RRAS2 gene (see, e.g., 600098.0001-600098.0003). The mutations arose de novo in the probands from 5 of the families.
In 3 of 219 individuals suspected of having Noonan syndrome (NS) or NS-related disorders, Niihori et al. (2019) identified heterozygosity for de novo mutations in the RRAS2 gene (see, e.g., 600098.0001 and 600098.0003). Functional analysis suggested that the mutations cause hyperactivation of the RAS/MAPK (see 176948) pathway.
Somatic Mutation
In epithelial ovarian tumor tissue (167000), Chan et al. (1994) identified a somatic missense mutation in the TC21 gene (Q72L; 600098.0001).
Using Rras2 -/- mice, Larive et al. (2012) found that Rras2 was dispensable for proper development and function of mouse organs, despite its widespread expression in wildtype mice. However, Rras2 was necessary for proper mammary gland development during the pubertal period, as full development of mammary gland was not achieved until the adult period in Rras2 -/- mice. Double- and triple-knockout experiments showed that Rras2, Hras (190020), and Nras (164790) were all important for kinetics of mammary gland development during the pubertal phase, but not for the overall developmental program of mammary gland, and that they did not act redundantly or additively. In vivo and in vitro analyses showed that Rras2 was expressed in both cap and epithelial cells of terminal end buds during pubertal development of mammary gland and was specifically involved in proliferation of mammary epithelial cells.
Martinez-Riano et al. (2019) found that Rras2 -/- mice showed a reduction in the percentage of Cd4 (186940)-positive/Cd8 (see 186910)-positive (i.e., double-positive) thymocytes compared with wildtype due to enhanced negative selection in thymocytes. Negative selection in thymocytes was due to defective Pi3k (see 601232)-Akt (164730) pathway activation, resulting in reduced T-cell receptor (TCR; see 186880) expression and resistance to autoimmune disorders, including a model of inflammatory bowel disease (IBD; see 266600) and experimental autoimmune encephalomyelitis (EAE). Analysis of the TCR repertoire in Rras2 -/- mice identified Trav4n3 and Trav4d3 (see 615442) as V-alpha variable sequences biased toward autoimmunity.
Noonan Syndrome 12
In an Indian boy (patient 4) who died at age 2 weeks with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a de novo germline c.215A-T transversion (c.215A-T, NM_012250.5) in the RRAS2 gene, resulting in a gln72-to-leu (Q72L) substitution within the switch II region. The mutation was not present in general population genetic databases. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see 601795) phosphorylation with the Q72L mutant compared to wildtype protein.
In a boy (patient HU1) with severe failure to thrive and features of Noonan syndrome, who died at age 3 years, Niihori et al. (2019) identified heterozygosity for the Q72L mutation (c.215A-T, NM_012250.6) in the RRAS2 gene. The mutation was shown to have arisen de novo. Functional analysis in HEK293T cells showed elevated association of RAF1 (164760) and activation of ERK1/2 (see 176948) and ELK1 (311040). Low-dose overexpression of the Q72L variant in zebrafish larvae resulted in a significantly increased ceratohyal angle compared to wildtype larvae; overexpression at higher dose caused lethal developmental impairments. Noting the severe phenotype present in patient HU1 compared to other RRAS2-mutated patients, as well as the more potent effects with the Q72L variant compared to other Noonan-associated RRAS2 variants in their in vitro and in vivo assays, the authors suggested a possible genotype/phenotype correlation.
Somatic Mutation in Ovarian Cancer
Chan et al. (1994) identified a somatic gln72-to-leu (Q72L) mutation in the TC21 gene in epithelial ovarian tumor tissue (167000) and demonstrated that the mutation was associated with high transforming activity.
In 4 affected members over 3 generations of a German family (family 3) with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a c.208G-A transition (c.208G-A, NM_012250.5) in the RRAS2 gene, resulting in an ala70-to-thr (A70T) substitution within the switch II region. The mutation, which was also identified in an 8-year-old Serbian girl (subject 5) with Noonan syndrome, was present in the gnomAD database in heterozygous state in 2 individuals (minor allele frequency, less than 0.00001). Biochemical analysis of the A70T mutant showed a significantly increased response to guanine nucleotide exchange factor (see 610215) compared to wildtype RRAS2, whereas the GTP hydrolysis reactions of the mutant were reduced compared to wildtype protein. In addition, binding to a RRAS2 effector, RASSF5 (607020), was abolished by the mutation. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see 601795) phosphorylation with the A70T mutant compared to wildtype RRAS2.
In a 22-month-old male infant of South American and Ashkenazi ancestry (patient 6) with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a de novo 9-bp duplication (c.70_78dup, NM_012250.5) in the RRAS2 gene, resulting in an in-frame duplication (Gly24_Gly26dup) within the phosphate-binding loop.
In a 6-year-old girl with Noonan syndrome (patient NS462), Niihori et al. (2019) identified heterozygosity for the c.70_78 duplication (c.70_78dup, NM_012250.6) in the RRAS2 gene, which was shown to have arisen de novo and was confirmed in hair and fingernails, consistent with a germline mutation. The authors noted that the duplication previously had been identified in a human uterine leiomyosarcoma cell line (SK-UT-1). Zebrafish larvae expressing the 9-bp duplication showed reduced body length, greater relative head length, and increased ceratohyal angle compared to wildtype larvae.
Capri, Y., Flex, E., Krumbach, O. H. F., Carpentieri, G., Cecchetti, S., Lissewski, C., Adariani, S. R., Schanze, D., Brinkmann, J., Piard, J., Pantaleoni, F., Lepri, F. R., and 21 others. Activating mutations of RRAS2 are a rare cause of Noonan syndrome. Am. J. Hum. Genet. 104: 1223-1232, 2019. [PubMed: 31130282] [Full Text: https://doi.org/10.1016/j.ajhg.2019.04.013]
Chan, A. M.-L., Miki, T., Meyers, K. A., Aaronson, S. A. A human oncogene of the RAS superfamily unmasked by expression cDNA cloning. Proc. Nat. Acad. Sci. 91: 7558-7562, 1994. [PubMed: 8052619] [Full Text: https://doi.org/10.1073/pnas.91.16.7558]
Drivas, G. T., Shih, A., Coutavas, E., Rush, M. G., D'Eustachio, P. Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line. Molec. Cell. Biol. 10: 1793-1798, 1990. [PubMed: 2108320] [Full Text: https://doi.org/10.1128/mcb.10.4.1793-1798.1990]
Gross, M. B. Personal Communication. Baltimore, Md. 1/3/2020.
Larive, R. M., Abad, A., Cardaba, C. M., Hernandez, T., Canamero, M., de Alva, E., Santos, E., Alarcon, B., Bustelo, X. R. The Ras-like protein R-Ras2/TC21 is important. Molec. Biol. Cell 23: 2373-2387, 2012. [PubMed: 22535521] [Full Text: https://doi.org/10.1091/mbc.E12-01-0060]
Martinez-Riano, A., Bovolenta, E. R., Boccasavia, V. L., Ponomarenko, J., Abia, D., Oeste, C. L., Fresno, M., van Santen, H. M., Alarcon, B. RRAS2 shapes the TCR repertoire by setting the threshold for negative selection. J. Exp. Med. 216: 2427-2447, 2019. [PubMed: 31324740] [Full Text: https://doi.org/10.1084/jem.20181959]
Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S., Tsai, I.-C., Matsumoto, N., Davis, E. E., Katsanis, N., Aoki, Y. Germline-activating RRAS2 mutations cause Noonan syndrome. Am. J. Hum. Genet. 104: 1233-1240, 2019. [PubMed: 31130285] [Full Text: https://doi.org/10.1016/j.ajhg.2019.04.014]