Alternative titles; symbols
HGNC Approved Gene Symbol: RASA1
Cytogenetic location: 5q14.3 Genomic coordinates (GRCh38): 5:87,267,883-87,391,916 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q14.3 | Basal cell carcinoma, somatic | 605462 | 3 | |
| Capillary malformation-arteriovenous malformation 1 | 608354 | Autosomal dominant | 3 |
The RAS gene family encodes membrane-associated, guanine nucleotide-binding proteins (p21) that are involved in the control of cellular proliferation and differentiation. Similar to other guanine-binding proteins (such as the heterotrimeric G proteins), the RAS proteins cycle between an active guanosine-triphosphate (GTP) bound form and an inactive, guanosine-diphosphate (GDP) bound form. The weak intrinsic GTPase activity of RAS proteins is greatly enhanced by the action of GTPase-activating proteins (GAPs), such as RASA1, which are effectors of RAS oncogene action (Trahey et al., 1988).
Trahey et al. (1988) purified RASA1 protein, which they called GAP, from placenta and obtained internal amino acid sequence of the protein from which they cloned 2 RASA1 transcripts. One transcript predicted a protein with molecular weight similar to purified GAP and corresponded to the human equivalent of bovine GAP cDNA. The other transcript predicted a smaller protein with a different N-terminal sequence, presumably the result of differential splicing. Both transcripts produced protein with GAP activity.
By the combination of somatic cell hybrid analysis and in situ hybridization, Hsieh et al. (1989) assigned the RASA1 gene to chromosome 5q13.3. Lemons et al. (1990) localized the RASA1 gene to chromosome 5q13-q15 by Southern analysis of somatic cell hybrids and by in situ hybridization.
Hsieh and Francke (1989) mapped the mouse Rasa1 gene to the distal end of chromosome 13.
Capillary Malformation-Arteriovenous Malformation 1
Starting with a family study of capillary malformation, or 'port-wine stain' (163000), Eerola et al. (2002, 2003) identified a susceptibility locus on 5q, which was initially referred to as CMC1. Eerola et al. (2003) screened for mutations in RASA1, which was a positional candidate, in 17 families. Heterozygous inactivating RASA1 mutations were detected in 6 families manifesting atypical capillary malformations associated with arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome. Eerola et al. (2003) named this new entity caused by RASA1 mutations 'capillary malformation-arteriovenous malformation' (CMAVM1; 608354). The phenotypic variability was thought to be explained by the involvement of p120-RasGAP in signaling for various growth factor receptors that control proliferation, migration, and survival of several cell types, including vascular endothelial cells.
Another inherited vascular malformation, cerebral capillary malformation (CCM; 116860), has also been related to misregulated Ras signaling. The mutated protein, KRIT1 (604214) was originally identified as a binding partner of Rap1a (179520), an antagonist of Ras transformation. KRIT1 has also been shown to bind ICAP1 (607153), a protein that links integrins and the actin cytoskeleton, which implies a process of integrin-signaling-mediated cellular adhesion in the pathogenesis of CCM. CMAVM and CCM may be due to similar cellular processes, since p120-RasGAP can bind Rap1a, which has an important role in integrin-mediated cellular adhesion. It is noteworthy that in certain families with CCM and mutations in KRIT1, some members also have cutaneous lesions characterized as hyperkeratotic capillary-venous malformations (Labauge et al., 1999; Eerola et al., 2000).
In affected members of 3 Ashkenazi Jewish families with capillary malformations, Hershkovitz et al. (2008) identified heterozygous mutations in the RASA1 gene (139150.0006-139150.0008). An arteriovenous malformation was only identified in 1 of the families, suggesting that the phenotypic spectrum of RASA1-related CMAVM can include patients with only capillary malformations.
In a combined retrospective and prospective study of 261 individuals with CMAVM and related phenotypes, Revencu et al. (2013) screened for mutations in the RASA1 gene and identified 58 in 68 of the 100 individuals with CMAVM and in none in those with related disorders, including 100 with common CMs, 37 with Sturge-Weber syndrome, and 24 with AVMs. The 68 CMAVM patients with mutations included 32 males and 36 females of European, Hispanic, or Asian ancestry; 7 of the patients had Parkes-Weber syndrome. The 58 mutations, 43 of which were novel, were predominantly truncating mutations; 52 were private mutations.
Revencu et al. (2013) analyzed DNA from a neurofibroma that had developed in a congenital Parkes-Weber lesion in a CMAVM patient with a previously confirmed germline mutation in the RASA1 gene. The DHPLC elution profile was indicative of loss of function of the wildtype allele in the tissue. SNP array showed mosaic loss of chromosome 5q, including the RASA1 gene, and part of chromosome 22, including the NF2 gene (607379). Sequencing of the NF2 gene revealed a nonsense mutation in the tissue, but not in the blood. The authors suggested that the 2 hits in the NF2 gene explain the development of the neurofibroma, and they speculated that the somatic loss of 5q, including the RASA1 gene, is involved in the pathogenesis of the Parkes Weber lesion.
Basal Cell Carcinoma, Somatic
Point mutations in RAS genes ('activating' or oncogenic mutants) decrease the intrinsic GTPase activity of RAS and are insensitive to stimulation by GAPs. This suggested to Friedman et al. (1993) that at least some of the transforming activity of mutant RAS is conferred by the RAS protein being constitutively activated in its GTP-bound state. Mutations in RAS that render it insensitive to GAP regulation result in tumor formation. Mutations in GAP that ablate its ability to downregulate RAS might result in a similar phenotype. To test this hypothesis, Friedman et al. (1993) analyzed 188 human tumor samples for mutations within the catalytic domain of the GAP gene and for mutations within its C-terminal SH2 region. Although no mutations could be demonstrated in the catalytic domain, 3 different nonsense mutations were observed in basal cell carcinomas. The region in which the mutations were clustered is A/T rich, raising the possibility that UV radiation is a contributing factor. The 3 mutations were found in the first 5 tumors examined. No abnormality was found in 16 other basal cell carcinomas. Thus, the apparent prevalence of GAP mutation was about 14% (3 of 21). The tumors analyzed included a great variety, including cancers of thyroid, lung, breast, colon, and pancreas. No GAP mutation was found in any of these. Mitsudomi et al. (1994) could not demonstrate mutations in the catalytic domain of the GAP gene in human lung cancer cell lines.
Lubeck et al. (2015) found that mice lacking both Nf1 (613113) and Rasa1 in T cells, but not those lacking either Nf1 or Rasa1 alone, developed T-cell acute lymphoblastic leukemia/lymphoma (see 613065) that originated at an early point in T-cell development and was dependent on activating mutations in Notch1 (190198). Lubeck et al. (2015) concluded that RASA1 and NF1 are co-tumor suppressors in the T-cell lineage.
Using denaturing gradient gel electrophoresis (DGGE) and direct sequence analysis, Friedman et al. (1993) screened a basal cell carcinoma tumor and identified a missense mutation in the SH2 domain of GAP. A change in codon 398 from CGA to CTA resulted in substitution of leucine for arginine.
Using DGGE and direct sequence analysis, Friedman et al. (1993) screened a basal cell carcinoma tumor and identified a missense mutation in the SH2 domain of GAP. A change in codon 400 from AAA to GAA resulted in substitution of glycine for lysine.
Using DGGE and direct sequence analysis, Friedman et al. (1993) screened a basal cell carcinoma tumor and identified a missense mutation in the SH2 domain of GAP. A change in codon 401 from ATA to GTA resulted in substitution of valine for isoleucine.
Eerola et al. (2003) described a family (PW1) with capillary malformation-arteriovenous malformation-1 (CMAVM1; 608354) in which the proband had Parkes Weber syndrome in the lower limb. Both parents and 1 grandparent on both sides of the family had capillary malformations. The brother of the proband had an intracranial arteriovenous malformation as well as multiple cutaneous capillary malformations. A 2-bp deletion in the RASA1 cDNA, 475_476delCT, was found, causing a frameshift and a premature stop codon at residue 178; the frameshift occurred at amino acid 159. The father of the proband, with a large facial capillary malformation, was pictured, as was a grandfather of the proband, who had a large nuchal capillary malformation. Neither of these individuals had the mutation in the RASA1 gene.
In their family CM11, Eerola et al. (2003) found association of capillary malformation-arteriovenous malformation (CMAVM1; 608354) with a missense mutation of the RASA1 cDNA: a 1619G-A transition predicted to result in a cys540-to-tyr (C540Y) amino acid change in the PH domain of the corresponding RASA1 protein. Eight individuals in 4 sibships in 2 generations of the family carried the mutation. One member of family CM11 had a facial capillary stain and hypertrophy distal to an arteriovenous fistula, which was located between the left carotid artery and the jugular vein and caused cardiac overload, requiring medication since infancy.
In affected members of an Ashkenazi Jewish family with capillary malformations (CMAVM1; 608354), Hershkovitz et al. (2008) identified a heterozygous 853C-T transition in the RASA1 gene, resulting in an arg285-to-ter (R285X) substitution.
In 2 twin brothers of Ashkenazi Jewish descent with capillary malformation-arteriovenous malformation (CMAVM1; 608354), Hershkovitz et al. (2008) identified a heterozygous G-to-A transition in intron 3 of the RASA1 gene (829-9G-A), resulting in a frameshift and premature termination. The proband had a small arteriovenous shunt in the outer ear.
In affected members of an Ashkenazi Jewish family with capillary malformations (CMAVM1; 608354), Hershkovitz et al. (2008) identified a heterozygous 4-bp duplication (2252dupTCAT) in the RASA1 gene, resulting in a frameshift and premature termination.
Eerola, I., Boon, L. M., Mulliken, J. B., Burrows, P. E., Dompmartin, A., Watanabe, S., Vanwijck, R., Vikkula, M. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am. J. Hum. Genet. 73: 1240-1249, 2003. [PubMed: 14639529] [Full Text: https://doi.org/10.1086/379793]
Eerola, I., Boon, L. M., Watanabe, S., Grynberg, H., Mulliken, J. B., Vikkula, M. Locus for susceptibility for familial capillary malformation ('port-wine stain') maps to 5q. Europ. J. Hum. Genet. 10: 375-380, 2002. [PubMed: 12080389] [Full Text: https://doi.org/10.1038/sj.ejhg.5200817]
Eerola, I., Plate, K. H., Spiegel, R., Boon, L. M., Mulliken, J. B., Vikkula, M. KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation. Hum. Molec. Genet. 9: 1351-1355, 2000. [PubMed: 10814716] [Full Text: https://doi.org/10.1093/hmg/9.9.1351]
Friedman, E., Gejman, P. V., Martin, G. A., McCormick, F. Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours. Nature Genet. 5: 242-247, 1993. [PubMed: 8275088] [Full Text: https://doi.org/10.1038/ng1193-242]
Hershkovitz, D., Bercovich, D., Sprecher, E., Lapidot, M. RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Brit. J. Derm. 158: 1035-1040, 2008. [PubMed: 18363760] [Full Text: https://doi.org/10.1111/j.1365-2133.2008.08493.x]
Hsieh, C. L., Francke, U. The gene for GTPase activating protein (GAP) is on human chromosome 5q and mouse chromosome 13. (Abstract) Cytogenet. Cell Genet. 51: 1016 only, 1989.
Hsieh, C. L., Vogel, U. S., Dixon, R. A., Francke, U. Chromosome localization and cDNA sequence of murine and human genes for ras p21 GTPase activating protein (GAP). Somat. Cell Molec. Genet. 15: 579-590, 1989. [PubMed: 2574500] [Full Text: https://doi.org/10.1007/BF01534919]
Labauge, P., Enjolras, O., Bonerandi, J.-J., Laberge, S., Dandurand, M., Joujoux, J.-M., Tournier-Lasserve, E. An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families. Ann. Neurol. 45: 250-254, 1999. [PubMed: 9989629] [Full Text: https://doi.org/10.1002/1531-8249(199902)45:2<250::aid-ana17>3.0.co;2-v]
Lemons, R. S., Espinosa, R., III, Rebentisch, M., McCormick, F., Ladner, M., Le Beau, M. M. Chromosomal localization of the gene encoding GTPase-activating protein (RASA) to human chromosome 5, bands q13-q15. Genomics 6: 383-385, 1990. [PubMed: 2307479] [Full Text: https://doi.org/10.1016/0888-7543(90)90581-e]
Lubeck, B. A., Lapinski, P. E., Oliver, J. A., Ksionda, O., Parada, L. F., Zhu, Y., Maillard, I., Chiang, M., Roose, J., King, P. D. Cutting edge: codeletion of the Ras GTPase-activating proteins (RasGAPs) neurofibromin 1 and p120 RasGAP in T cells results in the development of T cell acute lymphoblastic leukemia. J. Immun. 195: 31-35, 2015. [PubMed: 26002977] [Full Text: https://doi.org/10.4049/jimmunol.1402639]
Mitsudomi, T., Friedman, E., Gejman, P. V., McCormick, F., Gazdar, A. F. Genetic analysis of the catalytic domain of the GAP gene in human lung cancer cell lines. Hum. Genet. 93: 27-31, 1994. [PubMed: 8270251] [Full Text: https://doi.org/10.1007/BF00218908]
Revencu, N., Boon, L. M., Mendola, A., Cordisco, M. R., Dubois, J., Clapuyt, P., Hammer, F., Amor, D. J., Irvine, A. D., Baselga, E., Dompmartin, A., Syed, S., and 40 others. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum. Mutat. 34: 1632-1641, 2013. [PubMed: 24038909] [Full Text: https://doi.org/10.1002/humu.22431]
Trahey, M., Wong, G., Halenbeck, R., Rubinfeld, B., Martin, G. A., Ladner, M., Long, C. M., Crosier, W. J., Watt, K., Koths, K., McCormick, F. Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242: 1697-1700, 1988. [PubMed: 3201259] [Full Text: https://doi.org/10.1126/science.3201259]