Alternative titles; symbols
HGNC Approved Gene Symbol: HRAS
SNOMEDCT: 309776008;
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:532,242-535,576 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Bladder cancer, somatic | 109800 | 3 | |
| Congenital myopathy with excess of muscle spindles | 218040 | Autosomal dominant | 3 | |
| Costello syndrome | 218040 | Autosomal dominant | 3 | |
| Nevus sebaceous or woolly hair nevus, somatic | 162900 | 3 | ||
| Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic | 163200 | 3 | ||
| Spitz nevus or nevus spilus, somatic | 137550 | 3 | ||
| Thyroid carcinoma, follicular, somatic | 188470 | 3 |
The 3 RAS oncogenes, HRAS, KRAS (190070), and NRAS (164790), encode 21-kD proteins called p21s.
Wong-Staal et al. (1981) identified human DNA sequences homologous to cloned DNA fragments containing the oncogenic nucleic acid sequences of a type C mammalian retrovirus, the Harvey strain of murine sarcoma virus (HaMSV) derived from the rat. Non-onc intervening sequences were present in the human counterpart, which is rather highly conserved in mammalian evolution and probably plays a role in normal cell growth or differentiation. Allelic variation in the human onc HaMSV gene was identified. The transforming genes of retroviruses are derived from a group of cellular genes that are highly conserved evolutionarily. The relationship between viral transforming genes (collectively called v-onc) and their normal cellular counterparts (collectively called c-onc) is obviously of great scientific and medical interest. Chang et al. (1982) studied the Harvey and Kirsten murine sarcoma viruses, 2 closely related rat-derived transforming retroviruses called v-Ha-ras and v-Ki-ras, respectively. They concluded that the human genome contains several copies of the c-ras gene family and that c-Ha-ras-1 (with intervening sequences) (HRAS1) has been more highly conserved than has c-Ha-ras-2 (HRAS2; 300437).
By Southern blot analysis of human-rodent hybrid cell DNA, de Martinville et al. (1983) found that the cellular homolog of the transforming DNA sequence isolated from the bladder carcinoma line EJ is located on the short arm of chromosome 11. The locus also contains sequences homologous to the Harvey ras oncogene. No evidence of gene amplification was found. These workers also found karyologically 'a complex rearrangement of the short arm in two of the four copies of chromosome 11 present in this heteroploid cell line' (EJ). Region 11p15 was the site of a breakpoint in a t(3;11) translocation found in tumor cells from a patient with hereditary renal cell carcinoma (144700).
By in situ molecular hybridization studies of meiotic chromosomes (pachytene bivalents), Jhanwar et al. (1983) found that KRAS and HRAS probes mapped to chromomeres corresponding to bands 11p14.1, 12p12.1, and 12q24.2 of somatic chromosomes. HRAS hybridized most avidly at 11p14.1. A weak hybridization at 3p21.3 was noted.
By somatic cell hybridization, Junien et al. (1984) found that HRAS1 maps to 11p15.5-p15.1. The HRAS1 and insulin (INS; 176730) genes appear to be closely situated in the 11pter area; Gerhard et al. (1984) found a maximum lod score of 4.1 at theta = 0.0 for the HRAS1 and INS linkage. Two obligatory recombinants were found. These findings are consistent with the observation that the HRAS gene is not deleted in cases of Wilms tumor with deleted 11p13 (Junien et al., 1984). De Martinville and Francke (1984, 1984) likewise mapped HRAS1 and INS, and beta-globin (HBB; 141900) as well, outside the 11p14.1-p11.2 segment.
Fisher et al. (1984) concluded that HRAS1 is distal to the INS and HBB loci on 11p. Fearon et al. (1984) demonstrated that HRAS1 is 8 cM distal to the HBB gene and 4 cM proximal to the INS gene. The HBB gene is about 7 cM distal to the parathyroid hormone gene (PTH; 168450). The length of 11p is estimated to be about 50 cM.
By high resolution in situ hybridization to meiotic pachytene chromosomes, Chaganti et al. (1985) concluded that HRAS1 is located at 11p14.1, HBB at 11p11.22, PTH (not previously assigned regionally) at 11p11.21, and INS at 11p14.1.
Russell et al. (1996) constructed a contiguous physical map from the HRAS1 gene to the 11p telomere. The contig spanned approximately 500 kb. Three genes were placed on the contig in the following order: tel--RNH (173320)--HRAS1--HRC (142705).
Bianchi et al. (1993) mapped the H-ras-1 gene to the beta-globin region of mouse chromosome 7.
Goyette et al. (1983) found that the number of transcripts of the Harvey ras gene increases during liver regeneration in rats. This appeared to indicate regulated change in activity of an 'oncogene' in a physiologic growth process.
Ishii et al. (1985) pointed out similarities between the promoter of HRAS and that of epidermal growth factor receptor (EGFR; 131550). This similarity is intriguing in light of the finding of Hiwasa et al. (1988) that the preferential degradation of EGF receptors by cathepsin L (116880) may be suppressed by HRAS gene products (p21s).
Sears et al. (1999) showed that RAS enhances the accumulation of MYC (190080) activity by stabilizing the MYC protein. Whereas MYC has a very short half-life when produced in the absence of mitogenic signals, due to degradation by the 26S proteasome, the half-life of MYC increases markedly in growth-stimulated cells. This stabilization is dependent on the RAS/RAF/MAPK (see 176948) pathway and is not augmented by proteasome inhibition, suggesting that RAS inhibits the proteasome-dependent degradation of MYC. Sears et al. (1999) proposed that one aspect of MYC-RAS collaboration is an ability of RAS to enhance the accumulation of transcriptionally active MYC protein.
Hahn et al. (1999) found that ectopic expression of TERT (187270) in combination with 2 oncogenes, the simian virus 40 large-T oncoprotein and an oncogenic allele of HRAS (HRASV12), resulted in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrated that disruption of the intracellular pathways regulated by large-T, oncogenic RAS, and telomerase suffices to create a human tumor cell.
Mochizuki et al. (2001) used fluorescent resonance energy transfer (FRET)-based sensors to evaluate the spatiotemporal images of growth factor-induced activation of RAS and RAP1 (179520). Epidermal growth factor (131530) activated RAS at the peripheral plasma membrane and RAP1 at the intracellular perinuclear region of COS-1 cells. In PC12 cells, nerve growth factor (see 162030)-induced activation of RAS was initiated at the plasma membrane and transmitted to the whole cell body. After 3 hours, high RAS activity was observed at the extending neurites. By using the FRAP (fluorescence recovery after photobleaching) technique, Mochizuki et al. (2001) found that RAS at the neurites turned over rapidly; therefore, the sustained RAS activity at neurites was due to high GTP/GDP exchange rate and/or low GTPase activity, but not to the retention of the active RAS. While previous biochemical analyses rarely detected more than 40% activation of RAS upon growth factor stimulation, Mochizuki et al. (2001) concluded that their data show that growth factor stimulation strongly activates RAS/RAP1 in a very restricted area within cells, and that a large population of RAS or RAP1 remains inactive, causing an apparent low-level response in biochemical assays.
Zhu et al. (2002) examined the small GTPases RAS and RAP in the postsynaptic signaling underlying synaptic plasticity. They showed that RAS relays the NMDA receptor (see 138252) and calcium/calmodulin-dependent protein kinase II (see 114078) signaling that drives synaptic delivery of AMPA receptors (see 138248) during long-term potentiation. In contrast, RAP was found to mediate the NMDA receptor-dependent removal of synaptic AMPA receptors that occurs during long-term depression. The authors determined that RAS and RAP exert their effects on AMPA receptors that contain different subunit composition. Thus, RAS and RAP, whose activities can be controlled by postsynaptic enzymes, serve as independent regulators for potentiating and depressing central synapses.
Oft et al. (2002) found that activation of Smad2 (601366) induced migration of mouse squamous carcinoma cells, but that elevated levels of H-ras were required for nuclear accumulation of Smad2. Elevated levels of both were required for induction of spindle-cell transformation and metastasis.
Weijzen et al. (2002) demonstrated that oncogenic Ras activates Notch (190198) signaling and that wildtype Notch1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch1, and upregulates Notch1 ligand Delta1 (606582) and also presenilin-1 (104311), a protein involved in Notch processing, through a p38 (600289)-mediated pathway. Weijzen et al. (2002) concluded that their observations placed Notch signaling among key downstream effectors of oncogenic Ras.
Because therapeutics inhibiting RAS and NFKB (see 164011) pathways are used to treat human cancer, experiments assessing the effects of altering these regulators have been performed in mice. The medical relevance of murine studies is limited, however, by differences between mouse and human skin, and by the greater ease of transforming murine cells. To study RAS and NFKB in a setting more relevant to human tumorigenesis, Dajee et al. (2003) expressed the active HRAS gly12-to-val mutation (190020.0001), NFKB p65 (164014), and a stable NFKB repressor mutant of IKBA (164008) in human skin tissue. Primary human keratinocytes were retrovirally transduced and used to regenerate human skin on immune-deficient mice. Tissue expressing IKBA alone showed mild hyperplasia, whereas expression of oncogenic RAS induced growth arrest with graft failure. Although implicated in promoting features of neoplasia in other settings, the coexpression of oncogenic RAS with NFKB subunits failed to support proliferation. Coexpression of RAS and IKBA produced large neoplasms with deep invasion through fat into underlying muscle and fascia, similar to human squamous cell carcinomas (SCC), in 3 weeks. These tumors showed more than 10-fold increase in mitotic index, preserved telomeres, and increased amounts of TERT (187270) protein. Human keratinocytes lacking laminin-5 (LAMB3; 150310) and ITGB4 (147557) failed to form tumors on coexpression with RAS and IKBA; however, introduction of wildtype LAMB3 and ITGB4 restored tumor-forming capacity, suggesting that these 2 proteins are required for SCC tumorigenesis. Dajee et al. (2003) demonstrated that growth arrest triggered by oncogenic RAS can be bypassed by IKBA-mediated blockade of NFKB and that RAS opposed the increased susceptibility to apoptosis caused by NFKB blockade. Thus, IKBA circumvents restraints on growth promotion induced by oncogenic RAS and can act with RAS to induce invasive human tissue neoplasia.
Johnson et al. (2005) found that the 3 human RAS genes, HRAS, KRAS, and NRAS, contain multiple let-7 (605386) complementary sites in their 3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7 expression was lower in lung tumors than in normal lung tissue, whereas expression of the RAS proteins was significantly higher in lung tumors, suggesting a possible mechanism for let-7 in cancer.
Substitution of ser17 with asn (S17N) in any of the RAS proteins produces dominant-inhibitory proteins with higher affinities for exchange factors than normal RAS. These mutants cannot interact with downstream effectors and therefore form unproductive complexes, preventing activation of endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and canine kidney cells, Matallanas et al. (2003) found that the Hras, Kras, and Nras S17N mutants exhibited distinct inhibitory effects that appeared to be due largely to their specific membrane localizations. The authors demonstrated that Hras is present in caveolae, lipid rafts, and bulk disordered membranes, whereas Kras and Nras are present primarily in disordered membranes and lipid rafts, respectively. Thus, the Hras S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype Kras and the portion of Hras in disordered membranes, and the Nras S17N mutant inhibited wildtype Nras and the portion of Hras in lipid rafts.
Rocks et al. (2005) showed that the specific subcellular distribution of HRAS and NRAS guanosine triphosphate-binding proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated proteins, driving their rapid exchange between the plasma membrane and the Golgi apparatus. Depalmitoylation redistributes farnesylated Ras in all membranes, followed by repalmitoylation and trapping of Ras at the Golgi, from where it is redirected to the plasma membrane via the secretory pathway. This continuous cycle prevents Ras from nonspecific residence on endomembranes, thereby maintaining the specific intracellular compartmentalization. Rocks et al. (2005) found that the de/reacylation cycle also initiates Ras activation at the Golgi by transport of plasma membrane-localized Ras guanosine triphosphate. Different de/repalmitoylation kinetics account for isoform-specific activation responses to growth factors.
Di Micco et al. (2006) showed that senescence triggered by the expansion of an activated oncogene, HRAS V12, in normal human cells is a consequence of the activation of a robust DNA-damage checkpoint response. Experimental inactivation of this response abrogated oncogene-induced senescence and promoted cell transformation. DNA damage checkpoint response and oncogene-induced senescence were established after a hyperreplicative phase occurring immediately after oncogene expression. Senescent cells arrested with partly replicated DNA and with DNA replication origins having fired multiple times. In vivo DNA labeling and molecular DNA combing revealed that oncogene activation leads to augmented numbers of active replicons and to alterations in DNA replication fork progression. Di Micco et al. (2006) also showed that oncogene expression does not trigger a DNA damage checkpoint response in the absence of DNA replication. Last, Di Micco et al. (2006) showed that oncogene activation was associated with DNA damage checkpoint response activation in a mouse model in vivo. Di Micco et al. (2006) proposed that oncogene-induced senescence results from the enforcement of a DNA damage checkpoint response triggered by oncogene-induced DNA hyperreplication.
Zhang et al. (2006) showed that human HBP1 (616714) participated in RAS- and p38 MAPK-induced premature senescence. Knockdown of WIP1 (WIPF1; 602357) induced premature senescence in an HBP1-dependent manner. Zhang et al. (2006) proposed that RAS and p38 MAPK signaling engage HBP1 and RB (614041) to trigger premature senescence.
Ancrile et al. (2007) found that expression of an oncogenic form of HRAS induced secretion of the cytokine IL6 (147620) in normal primary human kidney cells, fibroblasts, myoblasts, and mammary epithelial cells. Knockdown of IL6, genetic ablation of the Il6 gene in mice, or treatment with IL6-neutralizing antibody retarded HRAS-driven tumorigenesis. IL6 appeared to act in a paracrine fashion to promote angiogenesis and tumor growth.
Stites et al. (2007) developed and validated a mathematical model of Ras signaling. The model-based predictions and associated experiments help explain why only 1 of 2 classes of activating Ras point mutations with in vitro transformation potential is commonly found in cancers. Model-based analysis of these mutants uncovered a systems-level process that contributes to total Ras activation in cells. This predicted behavior was supported by experimental observations. Stites et al. (2007) also used the model to identify a strategy in which a drug could cause stronger inhibition on the cancerous Ras network than on the wildtype network.
McMurray et al. (2008) showed that a large proportion of genes controlled synergistically by loss-of-function p53 (TP53; 191170) and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 of 24 'cooperation response genes' were found to contribute to tumor formation in gene perturbation experiments. In contrast, only 1 of 14 perturbations of the genes responding in a nonsynergistic manner had a similar effect. McMurray et al. (2008) concluded that synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations.
Lu et al. (2008) found that conditional activation of HRAS1(Q61L) in embryonic stem cells in vitro induced the trophectoderm marker Cdx2 (600297) and enabled derivation of trophoblast stem cell lines that, when injected into blastocysts, chimerized placental tissues. Erk2 (176948), the downstream effector of Ras-MAPK signaling, was asymmetrically expressed in the apical membranes of the 8-cell-stage embryo just before morula compaction. Inhibition of MAPK signaling in cultured mouse embryos compromised Cdx2 expression, delayed blastocyst development, and reduced trophectoderm outgrowth from embryo explants. Lu et al. (2008) concluded that ectopic Ras activation can divert embryonic stem cells toward extraembryonic trophoblastic fates and that Ras-MAPK signaling has a role in promoting trophectoderm formation from mouse embryos.
Gough et al. (2009) reported that malignant transformation by activated Ras (190020.0001) is impaired without STAT3 (102582), in spite of the inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation. Moreover, STAT3 mutants that cannot be tyrosine-phosphorylated, that are retained in the cytoplasm, or that cannot bind DNA nonetheless supported Ras-mediated transformation. Unexpectedly, STAT3 was detected within mitochondria, and exclusive targeting of STAT3 to mitochondria without nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3 sustained altered glycolytic and oxidative phosphorylation activities characteristic of cancer cells. Thus, Gough et al. (2009) concluded that, in addition to its nuclear transcriptional role, STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation.
By microarray analysis, Howe et al. (2017) found that microRNA-30B (MIR30B; 619018) was downregulated during VEGF (192240)-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). MIR30B negatively regulated HUVEC capillary morphogenesis, as MIR30B inhibition enhanced HUVEC capillary morphogenesis and MIR30B overexpression reduced it. MIR30B regulated HUVEC capillary morphogenesis by inducing TGFB2 expression in HUVECs in a manner dependent on activation of ATF2 (123811), a positive regulator of TGFB2 expression. The effect of MIR30B on ATF2 was indirect, as MIR30B directly targeted the ATF2 repressor JDP2 (608657). Increased expression of TGFB2 resulted in increased TGFB2 secretion and increased signaling downstream of TGF-beta receptors, which facilitated the inhibitory effects of MIR30B on capillary morphogenesis.
Somatic Mutations in Tumors
Der et al. (1982) found that mouse cells transformed by high molecular weight DNAs of a human bladder and a human lung carcinoma cell line contained new sequences homologous, respectively, to the transforming genes of Harvey (ras-H) and Kirsten (ras-K) sarcoma viruses. The HRAS1 oncogene differs from its normal cellular counterpart by the absence of a restriction endonuclease site. This sequence change could be used as the basis of a rapid screening method for this oncogene. Muschel et al. (1983) screened DNA from 34 persons and found that all were homozygous for the normal allele. On the other hand, DNA from a patient's bladder tumor, as well as DNA from his normal bladder and leukocytes, was heterozygous at that restriction endonuclease site. The change was pinpointed to 1 of 2 nucleotides, either of which would change the twelfth amino acid (glycine) in the normal HRAS1 gene product. Thus, the patient appeared to be carrying an HRAS1 mutation in his germline that predisposed him to bladder cancer. The restriction enzyme used in the screen was HpaII or its isoschizomer MspI. However, the authors retracted their data that purported to show an HRAS1 mutation in both tumor tissue and normal tissue; they concluded that the original extractions of DNA from that patient were contaminated by a plasmid DNA containing the HRAS1 oncogene. By restriction analysis, Feinberg et al. (1983) tested 29 human cancers for this mutation and found it in none. Included were 10 primary bladder cancers, 9 colon cancers, and 10 lung cancers. The point mutation altering the twelfth amino acid of the HRAS1 gene product p21, found in a bladder cancer cell line, was the only one known to result in a human transforming gene (see 190020.0001).
Capon et al. (1983) showed that the HRAS1 gene of the T24 human bladder carcinoma line has at least 4 exons and that only a single point mutation in the first exon distinguished the coding region of both alleles of the normal gene from their activated counterpart. Both versions of the gene encode a protein which is predicted to differ from the corresponding viral gene product at 3 amino acid residues, one of which was previously shown to represent the major site of phosphorylation of the viral polypeptide. Pincus et al. (1983) concluded that the bladder oncogene peptide (product of the mutant HRAS1 gene), with valine rather than glycine at position 12 (190020.0001), has a 3-dimensional structure markedly different from the normal. Tong et al. (1989) determined the structural change in the HRAS gene (called RASH by them) resulting from replacement of glycine 12 by valine.
Sekiya et al. (1984) found a point mutation in the second exon of the HRAS1 gene in a melanoma. Transversion from adenine to thymine resulted in the substitution of leucine for glutamine as amino acid 61 in the predicted p21 protein.
In 2 of 38 urinary tract tumors, Fujita et al. (1985) detected HRAS oncogenes by transfection, cloned the oncogene in biologically active form, and showed that it contained single base changes at codon 61 leading to substitutions of arginine and leucine, respectively, for glutamine at this position. In 1 tumor, a 40-fold amplification of KRAS was found. In the cell lines isolated from a single colon cancer, Greenhalgh and Kinsella (1985) found a point mutation in codon 12 of HRAS leading to an amino acid change in the gene product. The authors cited experience with KRAS involvement in 3 colon cancers and NRAS involvement in 1, while some 34 other colon cancers failed to demonstrate HRAS activation at codon 12.
Goriely et al. (2009) screened 30 spermatocytic seminomas (see 273300) for oncogenic mutations in 17 candidate genes and identified apparent homozygosity for 5 mutations in the HRAS gene (190020), 3 182A-G transitions and 2 181C-A transversions, all involving the Q61 codon (see, e.g., 190020.0002).
Yokota et al. (1986) concluded that alterations are found in oncogenes MYC (190080), HRAS, or MYB (189990) in more than one-third of human solid tumors. Amplification of MYC was found in advanced widespread tumors and in aggressive primary tumors. Apparent allelic deletions of HRAS and MYB could be correlated with progression and metastasis of carcinomas and sarcomas.
Corell and Zoll (1988) used the restriction enzymes MspI, HpaII, BamHI, and TaqI to analyze 426 alleles of the HRAS locus in DNA samples from 92 healthy individuals, 50 patients with breast cancer, 23 patients with ovarian cancer, and 5 patients with lymphomas. The allelic distribution was comparable among controls and tumor patients, indicating that a genetic predisposition to malignancy is not conferred by unique alleles at the HRAS locus. However, analysis of DNA isolated directly from tumors revealed a discrepancy between the alleles in the white blood cells and those in the tumor tissue. Six patients demonstrated alleles in the tumor tissue which were not observed in DNA from the white blood cells.
In a study of 118 lung cancer patients and 123 unaffected controls, Ryberg et al. (1990) found striking differences in the distribution of HRAS alleles. Six of 7 rare alleles were unique to the lung cancer group and 1 rare allele for the control group; rare alleles were found in 10 of 236 chromosomes in lung cancer patients as compared to 1 of 246 chromosomes in the controls. The lung cancer group also had a significantly lower frequency of 1 of the common alleles. The authors emphasized the importance of control for ethnic factors and the advantage in studying a relatively homogeneous population such as the Norwegian one.
The HRAS1 gene is tightly linked to a minisatellite located approximately 1 kb downstream from the gene's coding sequences and composed of 30 to 100 units of a 28-bp consensus sequence. Thirty alleles of 1,000 to 3,000 bp have been described. The 4 most common alleles--A1, A2, A3, and A4--represent 94% of all alleles in whites and have apparently served as progenitors for the remaining rare alleles. Rare alleles appear in the genomes of patients with cancer about 3 times as often as in controls without cancer (Krontiris et al., 1985); many such alleles have been observed only in patients with cancer. Krontiris et al. (1993) conducted a case-control study, typing 736 HRAS1 alleles from patients with cancer and 652 from controls by Southern blotting of leukocyte DNA. From analysis of the results and a meta-analysis of 22 other studies, they concluded that there was a significant association of rare HRAS1 alleles with 4 types of cancer: carcinomas of the breast, colorectum, and urinary bladder and acute leukemia. They considered it unlikely that the explanation could be found in linkage disequilibrium between these rare alleles and a pathogenetic lesion in the HRAS1 locus or other neighboring loci. Alternatively, they pointed to observations that new mutations of the HRAS1 minisatellite disrupt the controlled expression of nearby genes, including HRAS1, by interacting directly with transcriptional regulatory mechanisms. Furthermore, the minisatellite is capable of activating and repressing transcription; allele-specific effects have been observed.
Phelan et al. (1996) demonstrated a modifier effect of the HRAS1 locus on the penetrance of the BRCA1 gene (113705) in causing ovarian cancer. The polymorphism in question, a VNTR located 1 kb downstream of the HRAS1 gene, had previously been found to show an association between rare alleles and an increased risk of certain types of cancers, including breast cancer. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harboring 1 or 2 rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). A magnitude of the risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer. This study was said to have been the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.
Groesser et al. (2012) analyzed tissue from 65 individuals with nevus sebaceous (see 162900) for the presence of HRAS hotspot mutations. HRAS mutations were present in 62 lesions (95%), with a G13R substitution (190020.0017) accounting for 91%. Five sebaceous nevi carried 2 RAS mutations; the other gene involved was KRAS. Nonlesional tissue from 18 patients showed a wildtype HRAS sequence. Eight individuals developed secondary tumors within the nevus sebaceous, including 2 syringocystadenoma papilliferum, 3 trichoblastomas, and 3 trichilemmomas, and all secondary tumors carried the same mutation as the nevi. Functional analysis of mutant cells carrying the G13R mutation showed constitutive activation of the MAPK and PI3K (see 171834)/AKT (164730) signaling pathways. Other somatic HRAS mutations identified included G12S (190020.0003), G12D (190020.0013), and G12C (190020.0014). One patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) was found by Groesser et al. (2012) to carry the G13R mutation in the somatic mosaic state. The authors postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.
Hafner et al. (2012) found somatic activating RAS mutations in 28 (39%) of 72 keratinocytic epidermal nevi from 72 different individuals. HRAS was the most commonly mutated gene, found in 29% of all nevi, with G13R (190020.0017) being the most common mutation.
The HRAS G13R mutation was identified in Spitz nevi (see 137550) (Sarin et al., 2013) and in nevi spili (Sarin et al., 2014). Using microdissection techniques, Sarin et al. (2014) demonstrated that the G13R mutation was present in the melanocyte isolate but not in keratinocytes or dermal fibroblasts, suggesting that sporadic nevi spili result from postzygotic mutation in the melanocytic lineage.
By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic mutation in the HRAS gene (G12S; 190020.0003) in both individuals.
Genotype/Phenotype Correlations among Somatic HRAS, KRAS, and NRAS Mutations
In HRAS, KRAS, and NRAS, codons 12 and 61 are 'hotspots' for mutations that activate their malignant transforming properties. Srivastava et al. (1985) showed that mutation at these 3 loci result in changes in electrophoretic mobility of the p21. Changes observed are, for the HRAS gene, gly12 to val (bladder carcinoma), gly12 to asp (mammary carcinosarcoma), gln61 to leu (lung carcinoma), and gln61 to arg (renal pelvic carcinoma) and for the NRAS oncogene, gln61 to arg (lung carcinoma). They proposed that the electrophoretic changes may be a rapid method for identification of activated RAS genes, substituting for the inherently insensitive and time-consuming transfection assay.
Vasko et al. (2003) performed a pooled analysis of 269 mutations in HRAS, KRAS (190070), and NRAS (164790) garnered from 39 previous studies. Mutations proved significantly less frequent when detected with direct sequencing than without (12.3% vs 17%). The rates of mutation involving NRAS exon 1 and KRAS exon 2 was less than 1%. Mutations of codon 61 of NRAS were significantly more frequent in follicular tumors (19%) than in papillary cancers (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations in codon 61 were observed in only 1.4% of tumors, and almost all of them were malignant. KRAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs 1.6%) and were sometimes correlated with special epidemiologic circumstances. The second part of this study involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13 were found in 12.5% of common adenomas and 1 follicular carcinoma (2.9%). Mutations of codon 61 of NRAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. The authors concluded that their results confirmed the predominance of mutations of codon 61 of NRAS in thyroid follicular tumors and their correlation with malignancy.
Nikiforova et al. (2003) analyzed a series of 88 conventional follicular and Hurthle cell thyroid tumors for RAS (HRAS, NRAS, and KRAS) mutations and PAX8 (167415)-PPARG (601487) rearrangements using molecular methods and for galectin-3 (153619) and mesothelioma antibody HBME-1 expression by immunohistochemistry. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.
Costello Syndrome
Costello syndrome (218040), a multiple congenital anomaly and mental retardation syndrome, overlaps phenotypically with Noonan syndrome (163950), which is caused by mutation in the PTPN11 gene (176876) in approximately 50% of cases. The PTPN11 gene encodes tyrosine phosphatase SHP2; gain-of-function mutant SHP2 proteins identified in Noonan syndrome have enhanced phosphatase activity, which results in activation of a RAS-MAPK cascade in a cell-specific manner. Aoki et al. (2005) hypothesized that genes mutated in Costello syndrome and in PTPN11-negative Noonan syndrome encode molecules that function upstream or downstream of SHP2 in signal pathways. Among these molecules, they sequenced the entire coding region of 4 RAS genes in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN11-negative Noonan syndrome. In 12 of the 13 individuals with Costello syndrome, they found one or another of 4 heterozygous mutations in HRAS. These mutations had been identified somatically in various tumors (Bos, 1989). Mutation analysis of genomic DNA from 2 different tissues in 3 affected individuals and genomic DNA from parents in 4 families indicated that these 'oncogenic' and germline mutations occurred de novo. No mutations in KRAS, NRAS (164790), HRAS, or ERAS (300437) were observed in 28 individuals with Noonan syndrome or in 1 individual with Costello syndrome. Aoki et al. (2005) stated that, to the best of their knowledge, Costello syndrome was the first disorder associated with germline mutations in the RAS family of GTPases. The observations suggested that germline mutations in HRAS perturb human development and increase susceptibility to tumors.
Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S (190020.0003) was the most common mutation, found in 30 of the 37 mutation-positive patients. The authors stated that, together with previously published series (Aoki et al., 2005 and Gripp et al., 2006), mutations in HRAS had been found in 82 (85%) of 96 patients with a clinical diagnosis of Costello syndrome and that overall the frequency of malignancy in the published mutation-positive cases was 11%.
Costello syndrome can be caused by heterozygous de novo missense mutations affecting the codon for glycine-12 or glycine-13 of the HRAS gene. Sol-Church et al. (2006) identified 39 Costello syndrome patients harboring the gly12-to-ser mutation (190020.0003), the gly12-to-ala substitution (190020.0004), and 1 patient with the gly13-to-cys substitution (190020.0007). They conducted a search of the region flanking the mutated sites in 42 probands and 59 parents, and used 4 polymorphic markers to trace the parental origin of the germline mutations. One of the SNPs, rs12628 (81T-C), was found in strong linkage disequilibrium with a highly polymorphic hexanucleotide (GGGCCT) repeat region. Of a total of 24 probands with polymorphic markers, 16 informative families were tested and a paternal origin of the germline mutation was found in 14 Costello syndrome probands. This distribution was consistent neither with an equal likelihood of mutations arising in either parent (P = 0.0018), nor with exclusive paternal origin.
Zampino et al. (2007) identified the common G12S mutation in 8 of 9 unrelated patients with Costello syndrome; the ninth child had a different mutation (190020.0008). All mutations were de novo, paternally inherited, and associated with advanced paternal age. None of 36 patients with Noonan syndrome or 4 with cardiofaciocutaneous syndrome (CFCS; 115150) had a mutation in the HRAS gene.
Lo et al. (2008) described 4 infants with an unusually severe Costello syndrome phenotype and 3 different mutations in the HRAS gene: the common G12S mutation (190020.0003) was seen in 1 case, 2 cases had a G12D mutation (190020.0013), and 1 case had a G12C mutation (190020.0014).
Gremer et al. (2010) reported 2 different 3-nucleotide duplications in the first coding exon of the HRAS gene (exon 2) resulting in a duplication of glutamate-37 (E37dup) associated with a phenotype reminiscent of Costello syndrome. None of the parents carried the mutations. The phenotype of the 2 affected individuals was remarkably similar and characterized by severe mental retardation and pronounced short stature in one (190020.0015) and relatively mild involvement of the musculoskeletal system compared with the classical Costello syndrome phenotype in the other (190020.0016). Ectopic expression of HRAS(E37dup) in COS-7 cells resulted in enhanced growth factor-dependent stimulation of the MEK-ERK (see MEK1, 176872) and phosphoinositide 3-kinase (PI3K; 601232)-AKT (164730) signaling pathways. Recombinant HRAS(E37dup) was characterized by slightly increased GTP/GDP dissociation, lower intrinsic GTPase activity, and complete resistance to neurofibromin-1 GTPase-activating protein (NF1; 613113) stimulation due to dramatically reduced binding. Coprecipitation of GTP-bound HRAS(E37dup) by various effector proteins, however, was inefficient because of drastically diminished binding affinities. Thus, although HRAS(E37dup) was predominantly present in the active, GTP-bound state, it promoted only a weak hyperactivation of downstream signaling pathways. The authors proposed that the mildly enhanced signal flux through the MAPK and PI3K-AKT cascades promoted by these disease-causing germline HRAS alleles may result from a balancing effect between a profound GAP insensitivity and inefficient binding to effector proteins.
Carpentieri et al. (2022) evaluated metabolic dysregulation in primary fibroblasts from 6 individuals with Costello syndrome and heterozygous mutations in the HRAS gene. Fibroblasts from the patients demonstrated increased rates of glucose uptake and glycolysis compared to controls, without evidence for a defect in oxidative phosphorylation. The increased glucose uptake in the cells was correlated to increased fatty acid synthesis and lipid droplet accumulation and was associated with increased expression and constitutive plasma membrane translocation of the GLUT4 transporter. Carpentieri et al. (2022) hypothesized that this metabolic dysregulation may represent a factor in lower blood sugar and increased fat stores observed in patients with Costello syndrome. Patient fibroblasts also had increased steady-state autophagy. Carpentieri et al. (2022) hypothesized that both increased autophagy and increased GLUT4 expression could be due to increased AMP-activated protein kinase-alpha and p38 signaling triggered by increased reactive oxidant species.
Dard et al. (2022) evaluated mitochondrial function in skin fibroblasts and iPSC-derived cardiomyocytes from patients with Costello syndrome and heterozygous G12S (190020.0003) or G12A (190020.0004) mutations in the HRAS gene, and control fibroblasts with induced expression of HRAS with the G12S or G12A mutations. Bioenergetic studies demonstrated that most of the ATP produced in the induced cardiomyocytes from the patients was derived from glycolysis. In the fibroblast models, Dard et al. (2022) found altered expression of mediators of autophagy and mitochondrial biogenesis, suggesting abnormal mitochondrial proteostasis. These abnormalities were attributed to inhibition of AMPK signaling pathways by mutant HRAS.
Congenital Myopathy with Excess Muscle Spindles
Van der Burgt et al. (2007) identified mutations in the HRAS gene (190020.0001; 190020.0003; 190020.0009; 190020.0010) in patients with congenital myopathy with excess muscle spindles, a variant of Costello syndrome.
Schuhmacher et al. (2008) generated a mouse model of Costello syndrome by introduction of an oncogenic gly12-to-val mutation (190020.0001) in the mouse Hras gene. Mutant mice developed hyperplasia of the mammary gland, but tumor development was rare. The mice showed some phenotypic features similar to those in patients with Costello syndrome, including facial dysmorphism and cardiomyopathy. Mutant mice also developed systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys resulting from abnormal upregulation of the renin-angiotensin II system, which responded to treatment with captopril. Histologic studies with a tagged wildtype Hras gene showed expression in most murine embryonic tissues and several adult tissues, including the heart, aortic vascular smooth muscle cells, kidney, mammary glands, skin epithelium, urinary bladder, colon, and brain.
Using an Hras knockin mouse model, To et al. (2008) demonstrated that specificity for Kras (190070) mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target Ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The 2 Kras isoforms undergo different posttranslational modifications. To et al. (2008) concluded that their findings may have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.
In a mouse model with a heterozygous knockin for a G12S mutation in the HRAS gene, Dard et al. (2022) observed left ventricular cardiac hypertrophy at 23 weeks of age. In heart muscle fibers from 12-week-old mutant mice, there was a generalized decrease in mitochondrial respiratory chain complex I-IV, and in skeletal muscle fibers there was a reduction in state 3 respiration and mitochondrial ATP synthesis. Proteomics studies in mouse tissues, including heart and liver, demonstrated reduced expression of fatty acid oxidation and AMPK targets, which Dard et al. (2022) suggested led to altered mitochondrial proteostasis and bioenergetics.
Bladder Cancer, Somatic
Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, while the same gene cloned from normal cellular DNA did not. Furthermore, they showed that the change in the transforming gene was a single nucleotide substitution that produced change of a single amino acid in the sequence of the protein that the gene encodes. They suggested that antibodies against Ras proteins might be diagnostic for certain forms of cancer. The T24 gene had a change from GGC (glycine) to GTC (valine) as codon 12. Fearon et al. (1985) examined constitutional and tumor genotypes at loci on the short arm of chromosome 11 in 12 patients with transitional cell carcinomas of the bladder. In 5 they found loss of genes in the tumor, resulting in homozygosity or hemizygosity of the remaining allele. This frequency (42%) approached that seen in Wilms tumor (55%).
The G12V mutant of HRAS had the lowest GTPase activity among various substitutions at codon 12 (Colby et al., 1986), and biologic assays by focus formation in NIH3T3 cells or soft agar growth showed that this substitution had the highest transformation potential among substitutions tested at this codon (Seeburg et al., 1984, Fasano et al., 1984). Aoki et al. (2005) noted that among codon 12 HRAS mutations found somatically in human cancers, G12V is the predominant mutation.
Epidermal Nevus, Somatic
Hafner et al. (2012) identified a somatic G12V mutation in 1 of 72 keratinocytic epidermal nevi (162900).
Costello Syndrome
In a Japanese patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35GC-TT nucleotide substitution in the HRAS gene that resulted in a gly12-to-val amino acid change (G12V). This individual died of severe cardiomyopathy at 18 months of age.
Congenital Myopathy with Excess of Muscle Spindles
Van der Burgt et al. (2007) identified a heterozygous G12V mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a variant of Costello syndrome. The patient, originally reported by de Boode et al. (1996), died at age 3 weeks. He was a preterm infant with generalized hypotonia and progressive hypertrophic obstructive cardiomyopathy.
Follicular Thyroid Carcinoma, Somatic
Nikiforova et al. (2003) found that a CAG-to-AAG change at HRAS codon 61, resulting in a gln-to-lys amino acid change (Q61K), was present in 2 follicular carcinomas (see 188550), 2 follicular adenomas, and 1 Hurthle cell adenoma, accounting for 12%, 18%, and 100% of each tumor type examined, respectively.
Spermatocytic Seminoma, Somatic
Goriely et al. (2009) screened 30 spermatocytic seminomas (see 273300) for mutations in 17 candidate genes, and in 2 tumors they identified apparent homozygosity for a C-A transversion in the HRAS gene that resulted in the Q61K substitution.
Costello Syndrome
In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution.
Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients.
Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous.
In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age.
Congenital Myopathy with Excess of Muscle Spindles
Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet.
Epidermal Nevus and Urothelial Cancer, Somatic
Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung.
Nevus Sebaceous, Somatic
Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900).
Woolly Hair Nevus, Somatic
By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus.
In 1 Japanese and 1 Italian patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35G-C transversion in the HRAS gene that caused a gly12-to-ala (G12A) amino acid substitution.
In 2 Japanese patients with Costello syndrome (218040), Aoki et al. (2005) found a germline 38G-A transition in the HRAS gene that caused a gly13-to-asp (G13D) amino acid substitution.
In a 9-year-old girl with Costello syndrome (218040), Kerr et al. (2006) identified a de novo 350A-G transition in the HRAS gene, resulting in a lys117-to-arg (K117R) substitution. The patient's physical phenotype was unusual in that she had microretrognathism and both her plantar and palmar creases were less pronounced than usually seen in Costello syndrome. Her behavioral phenotype included autistic traits with verbal stereotypies and hand biting. Otherwise she had classic features of Costello syndrome with cardiac involvement (cardiomyopathy and ventricular septal defect) but no neurologic malformation. The mutation was not found in either of her parents.
Denayer et al. (2008) identified a de novo K117R mutation in a 6-year-old girl with typical Costello syndrome. Behavioral features included moderate mental retardation with a friendly personality and no autistic features. In vitro functional expression studies showed increased levels of phosphorylated proteins consistent with constitutive activation of the RAS/MAPK pathways. Recombinant K117R showed normal intrinsic GTP hydrolysis and responsiveness to GTPase-activating proteins, but the nucleotide disassociation rate was increased 80-fold. Crystal structure data indicated an altered interaction pattern of the side chain that was associated with unfavorable nucleotide binding properties.
Sol-Church et al. (2006) found that 1 of 42 patients with Costello syndrome (218040) and heterozygous de novo missense mutations involving either glycine-12 or -13 of the HRAS gene carried a gly13-to-cys (G13C) substitution (37G-A).
Piccione et al. (2009) reported a premature male infant born at 29 weeks' gestation due to fetal distress who was found to have Costello syndrome due to the G13C mutation. The characteristic facial features were not apparent until about 4 months of age, when he was noted to have relative macrocephaly, coarse face with hypertelorism, downslanting palpebral fissures, epicanthal folds, prominent eyes, short nose, low-set ears, large mouth, short neck, loose skin of hands and feet, sparse hair, hyperpigmented skin, deep palmar creases, joint laxity, reduced subcutaneous adipose tissue, and bilateral cryptorchidism. At 11 months of age, he had delayed motor development with central hypotonia, but adequate mental and speech development. Papillomata were not present. Piccione et al. (2009) noted that the distinctive features of Costello syndrome may be absent during the first months of life, especially in preterm infants who often have failure to thrive and decreased subcutaneous adipose tissue. The striking facial features of the disorder become more evident after the critical neonatal period.
Gripp et al. (2011) examined 12 individuals with Costello syndrome due to the G13C mutation and compared the phenotype to those with the G12S (190020.0003) mutation. Individuals with G13C had many typical findings including polyhydramnios, failure to thrive, hypertrophic cardiomyopathy, macrocephaly, posterior fossa crowding, and developmental delay. Their facial features were less coarse and short stature was less severe. Statistically significant differences included the absence of several common features, including multifocal atrial tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy absence of malignant tumors did not reach statistical significance. There were some novel ectodermal findings associated with the G13C mutation, including loose anagen hair and long eyelashes requiring trimming (termed 'dolichocilia').
In 1 of 9 unrelated patients with Costello syndrome (218040), Zampino et al. (2007) identified a de novo 436G-A transition in the HRAS gene, resulting in an ala146-to-thr (A146T) substitution. The mutation was of paternal origin. The patient had unusual features, including normal neonatal growth, microcephaly, normal ears, and thin, but not curly, hair. Crystallographic information indicated that the A146T substitution occurs in a hydrophobic pocket involved in binding to the purine ring of GTP/GDP and likely destabilizes the binding of GTP and GDP. Since GTP has a higher cytoplasmic concentration and would therefore be more likely to bind to the protein, the A146T mutation may result in a gain of function.
In a 7-month-old girl with congenital myopathy with excess of muscle spindles (see 218040), a variant of Costello syndrome, van der Burgt et al. (2007) identified a heterozygous 187G-A transition in the HRAS gene, resulting in a glu63-to-lys (E63K) substitution. The patient, originally reported by Stassou et al. (2005), had hypertrophic obstructive cardiomyopathy, hypotonia, contractures, and clubfeet, and died at age 7 months of respiratory failure.
In a 13-month-old boy with congenital myopathy with excess of muscle spindles (see 218040), a variant of Costello syndrome, van der Burgt et al. (2007) identified a heterozygous 64C-A transversion in the HRAS gene, resulting in a gln22-to-lys (Q22K) substitution. The patient had mild hypertrophic cardiomyopathy, generalized hypotonia, delayed motor development, and poor feeding.
In a boy with Costello syndrome (218040), Gripp et al. (2008) identified a heterozygous de novo 173C-T transition in exon 3 of the HRAS gene, resulting in a thr58-to-ile (T58I) substitution in a highly conserved residue in the switch II region of small GTPases. Neither parent carried the mutation, which was present on the paternal allele. At the time of birth, the father and mother were 45 and 34 years old, respectively. The facial features of the patient were less coarse than typical Costello syndrome, but he showed other typical features, including failure to thrive, cognitive impairment, lax skin, deep palmar creases, and pyloric stenosis.
In a girl with Costello syndrome (218040), Gripp et al. (2008) identified a heterozygous 437C-T transition in exon 4 of the HRAS gene, resulting in an ala146-to-val (A146V) substitution. The facial features of the patient were less coarse than usually seen in Costello syndrome, but she also showed other typical features, including hypertrophic cardiomyopathy, deep palmar creases, and delayed development. Another HRAS mutation resulting in Costello syndrome has been reported in this codon (A146T; 190020.0008).
Costello Syndrome
In 2 infants with severe Costello syndrome (218040) including neonatal hypoglycemia and respiratory failure, Lo et al. (2008) identified 35G-A transition in the HRAS gene, resulting in a gly12-to-asp (G12D) substitution. One infant had paroxysmal multifocal atrial tachycardia, atrial septal defect, and septal hypertrophy, as well as persistent respiratory distress with tracheobronchomalacia, recurrent pneumothorax, pneumonia, and chylothorax, and died at age 3 months due to respiratory failure; postmortem lung histology showed findings consistent with lymphangiectasia and alveolar/capillary dysplasia. The other infant had hypertrophic cardiomyopathy and dysplastic pulmonary valve noted at day 1, and developed atrial fibrillation and heart failure at day 35; she had persistent hyponatremia due to renal sodium leakage with signs of renal failure at 6 weeks. She became ventilator dependent and died at 3 months of age from sepsis and renal failure.
Kuniba et al. (2009) reported a Japanese fetus with severe Costello syndrome due to the G12D mutation. He was diagnosed using prenatal 3-dimensional ultrasonography at 23 weeks' gestation. Findings at that time included polyhydramnios, severe overgrowth (+5.3 SD using a Japanese fetal growth curve), and dysmorphic craniofacial features, such as large head, pointed chin, broad nasal bridge, and low-set ears. In addition, the wrists showed lateral deviation and flexion. After birth, he developed respiratory failure, severe hypoglycemia, cardiac hypertrophy, and renal failure, and died soon after birth. The phenotype was similar to that reported by Lo et al. (2008) in 2 infants with the G12D mutation, suggesting that this mutation is associated with a severe clinical outcome and death in early infancy.
Nevus Sebaceous, Somatic
Groesser et al. (2012) identified a somatic G12D mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900).
Costello Syndrome
In a male infant with severe Costello syndrome (218040), Lo et al. (2008) identified a 34G-T transversion in the HRAS gene, resulting in a gly12-to-cys (G12C) substitution. The patient developed respiratory distress after delivery and required intubation and ventilatory support secondary to small lungs and upper airway obstruction. He had an atrial tachyarrhythmia with apparent thickening of the myocardial wall and redundant mitral valve tissue on echocardiogram, and had echogenic kidneys with thick-walled pelvises on ultrasound. He died at 3 months of age due to respiratory failure.
Nevus Sebaceous, Somatic
Groesser et al. (2012) identified a somatic G12C mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900).
Epidermal Nevus, Somatic
Hafner et al. (2012) identified a somatic G12C mutation in 1 of 72 keratinocytic epidermal nevi (162900).
In a 5-year-old Kurdish male with a phenotype reminiscent of Costello syndrome (218040), Gremer et al. (2010) detected a heterozygous 3-bp duplication in exon 2 of the HRAS gene that resulted in duplication of glutamic acid at position 37 (110_111+1dupAGG, glu37dup). The child had hypertrophic cardiomyopathy, global developmental delay, growth retardation, coarse facial features, and sparse hair. Mental retardation was severe, with no speech development. Neither parent carried the mutation. The authors also identified another patient with a similar phenotype who also carried a duplication of glu37 caused by a different 3-nucleotide duplication (190020.0016).
In a 6-year-old Italian boy with a phenotype reminiscent of Costello syndrome (218040), Gremer et al. (2010) detected a heterozygous 3-bp duplication in exon 2 of the HRAS gene that resulted in duplication of glutamic acid at position 37 (108_110dupAGA, glu37dup). The patient had global developmental delay, growth retardation, coarse facial features, sparse hair, and a thickened ventricular septum. Language was absent. Neither of his parents carried the mutation. Another duplication of glu37 was identified in another patient (190020.0015).
Nevus Sebaceous, Somatic
In 59 (91%) of 65 different nevus sebaceous (see 162900) tumors, Groesser et al. (2012) identified a somatic 37G-C transversion in the HRAS gene, resulting in a gly13-to-arg (G13R) substitution. Two of the tumors also carried a somatic mutation in the KRAS gene (190070.0005 and 190070.0006, respectively), and 1 tumor had 2 HRAS mutations: G13R and G12S (190020.0003). Nonlesional tissue from 18 individuals with the G13R mutation showed the wildtype HRAS allele. Eight individuals developed secondary tumors within the nevus sebaceous, including 2 syringocystadenoma papilliferum, 3 trichoblastomas, and 3 trichilemmomas, and all secondary tumors carried the same mutation as the nevi, suggesting that they arose from cells of the nevus sebaceous. Functional analysis of mutant cells carrying the G13R mutation showed constitutive activation of the MAPK and PI3K-AKT signaling pathways.
Levinsohn et al. (2014) screened 116 archival scalp nevus sebaceous lesions and detected the HRAS G13R mutation in 85 specimens.
Epidermal Nevus, Somatic
Hafner et al. (2012) identified a somatic G13R mutation in 21 of 24 HRAS-mutant keratinocytic epidermal nevi (162900), making it the most common mutation among a larger series of 72 nevi.
Spitz Nevus and Nevus Spilus, Somatic
The HRAS G13R mutation was identified in Spitz nevi (see 137550) (Sarin et al., 2013) and in nevi spili (Sarin et al., 2014). Using microdissection techniques, Sarin et al. (2014) demonstrated that the G13R mutation was present in the melanocyte isolate but not in keratinocytes or dermal fibroblasts, suggesting that sporadic nevi spili result from postzygotic mutation in the melanocytic lineage.
Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic
One patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) was found by Groesser et al. (2012) to carry the G13R mutation in somatic mosaic state. This patient had originally been reported by Zutt et al. (2003). She was a 52-year-old woman who was noted at birth to have a large, right-sided nevus sebaceous extending to her head, neck, arm, and trunk. The scalp was also involved, resulting in alopecia. The patient developed recurrent syringocystadenoma papilliferum and basal cell carcinoma within the nevus. Other features included generalized growth retardation, hypophosphatemic rickets, and precocious puberty. Intelligence was normal. There was no family history of a similar disorder.
Lim et al. (2014) identified a patient with SFM who had marked elevation of serum FGF23 (605380) and hypophosphatemia who carried the somatic activating HRAS mutation G13R in affected bone and skin.
In an 18-year-old girl, born of consanguineous Turkish parents, with a relatively mild form of Costello syndrome (218040), Lorenz et al. (2013) identified a de novo heterozygous 21-bp duplication (c.187_207dup) in exon 3 of the HRAS gene, resulting in the duplication of amino acids 63 to 69 (E63_D69dup). Five of these residues are an integral part of the HRAS switch II domain that mediates binding of HRAS with various regulator and effector proteins. In vitro cellular functional expression studies showed that the E63_D69dup mutation increases HRAS coprecipitation with certain effector proteins, but not with PIK3CA (171834). Overexpression of the mutant protein increased steady-state phosphorylation of downstream effectors MEK1/2 and ERK1/2, but not AKT. The mutant protein had some residual response to EGF stimulus compared to constitutively active HRAS mutations. The findings indicated that this duplication mutant has a gain-of-function effect for some effectors, but this is counteracted by a normal effect on PIK3CA signaling. The patient had mildly delayed psychomotor development as a child, as well as hypertrophic cardiomyopathy, osteoporosis, coarse facial features, short stature, hyperkeratotic skin lesions, pigmentary anomalies, and mild intellectual disability. Lorenz et al. (2013) concluded that the attenuated phenotype in this patient was due to impaired regulator and effector binding of the E63_D69dup mutant.
Lim et al. (2014) reported a 15-year-old black female with widespread keratinocytic epidermal nevi (SFM; 163200) on the torso and sebaceous nevi on the scalp and cheek, with brown verrucous papules and plaques covering the scalp, face, torso, and extremities as well as linear white plaques on the scalp and torso. Histopathologic examination showed marked sebaceous hyperplasia, hyperkeratosis, and papillomatosis. In affected skin and affected bone, Lim et al. (2014) identified a c.182A-G transition in the HRAS gene, resulting in a gln61-to-arg (Q61R) substitution. The mutation was not found in the germline. None of the skin samples demonstrated expression of FGF23 (605380), but the dysplastic bone demonstrated very high FGF23 expression.
Ancrile, B., Lim, K.-H., Counter, C. M. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 21: 1714-1719, 2007. [PubMed: 17639077] [Full Text: https://doi.org/10.1101/gad.1549407]
Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature Genet. 37: 1038-1040, 2005. [PubMed: 16170316] [Full Text: https://doi.org/10.1038/ng1641]
Bianchi, A. B., Rinchik, E. M., Conti, C. J. Reassignment of the H-ras-1 gene to the Hbb-terminus region of mouse chromosome 7. Mammalian Genome 4: 220-222, 1993. [PubMed: 8499656] [Full Text: https://doi.org/10.1007/BF00417566]
Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49: 4682-4689, 1989. Note: Erratum: Cancer Res. 50: 1352 only, 1990. [PubMed: 2547513]
Capon, D. J., Chen, E. Y., Levinson, A. D., Seeburg, P. H., Goeddel, D. V. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature 302: 33-37, 1983. [PubMed: 6298635] [Full Text: https://doi.org/10.1038/302033a0]
Carpentieri, G., Leoni, C., Pietraforte, D., Cecchetti, S., Iorio, E., Belardo, A., Pietrucci, D., Di Nottia, M., Pajalunga, D., Megiorni, F., Mercurio, L., Tatti, M., and 11 others. Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species. Hum. Molec. Genet. 31: 561-575, 2022. [PubMed: 34508588] [Full Text: https://doi.org/10.1093/hmg/ddab270]
Chaganti, R. S. K., Jhanwar, S. C., Antonarakis, S. E., Hayward, W. S. Germ-line chromosomal localization of genes in chromosome 11p linkage: parathyroid hormone, beta-globin, c-Ha-ras-1, and insulin. Somat. Cell Molec. Genet. 11: 197-202, 1985. [PubMed: 3885418] [Full Text: https://doi.org/10.1007/BF01534708]
Chang, E. H., Gonda, M. A., Ellis, R. W., Scolnick, E. M., Lowy, D. R. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc. Nat. Acad. Sci. 79: 4848-4852, 1982. [PubMed: 6289320] [Full Text: https://doi.org/10.1073/pnas.79.16.4848]
Colby, W. W., Hayflick, J. S., Clark, S. G., Levinson, A. D. Biochemical characterization of polypeptides encoded by mutated human Ha-ras1 genes. Molec. Cell. Biol. 6: 730-734, 1986. [PubMed: 3537694] [Full Text: https://doi.org/10.1128/mcb.6.2.730-734.1986]
Corell, B., Zoll, B. Comparison between the allelic frequency distribution of the Ha-ras-1 locus in normal individuals and patients with lymphoma, breast, and ovarian cancer. Hum. Genet. 79: 255-259, 1988. [PubMed: 2841224] [Full Text: https://doi.org/10.1007/BF00366247]
Dajee, M., Lazarov, M., Zhang, J. Y., Cai, T., Green, C. L., Russell, A. J., Marinkovich, M. P., Tao, S., Lin, Q., Kubo, Y., Khavari, P. A. NF-kappa-B blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421: 639-643, 2003. [PubMed: 12571598] [Full Text: https://doi.org/10.1038/nature01283]
Dard, L., Hubert, C., Esteves, P., Blanchard, W., About, G. B., Baldasseroni, L., Dumon, E., Angelini, C., Delourme, M., Guyonnet-Duperat, V., Claverol, S., Fontenille, L., and 11 others. HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models. J. Clin. Invest. 132: e131053, 2022. [PubMed: 35230976] [Full Text: https://doi.org/10.1172/JCI131053]
de Boode, W. P., Semmekrot, B. A., ter Laak, H. J., van der Burgt, C. J. A. M, Draaisma, J. M. T., Lommen, E. J. P, Sengers, R. C. A., van Wijk-Hoek, J. M. Myopathology in patients with a Noonan phenotype. Acta Neuropath. 92: 597-602, 1996. [PubMed: 8960317] [Full Text: https://doi.org/10.1007/s004010050566]
de Martinville, B., Francke, U. The c-Ha-ras1, insulin and beta-globin loci map outside the deletion associated with aniridia-Wilms' tumour. Nature 305: 641-643, 1983. [PubMed: 6312329] [Full Text: https://doi.org/10.1038/305641a0]
de Martinville, B., Francke, U. HRAS1, insulin, and beta-globin map outside of 11p11.2-11p14.1. (Abstract) Cytogenet. Cell Genet. 37: 530, 1984.
de Martinville, B., Giacalone, J., Shih, C., Weinberg, R. A., Francke, U. Oncogene from human EJ bladder carcinoma is located on the short arm of chromosome 11. Science 219: 498-501, 1983. [PubMed: 6297001] [Full Text: https://doi.org/10.1126/science.6297001]
Denayer, E., Parret, A., Chmara, M., Schubbert, S., Vogels, A., Devriendt, K., Frijns, J.-P., Rybin, V., de Ravel, T. J., Shannon, K., Cools, J., Scheffzek, K., Legius, E. Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.lys117arg mutation. Hum. Mutat. 29: 232-239, 2008. [PubMed: 17979197] [Full Text: https://doi.org/10.1002/humu.20616]
Der, C. J., Krontiris, T. G., Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc. Nat. Acad. Sci. 79: 3637-3640, 1982. [PubMed: 6285355] [Full Text: https://doi.org/10.1073/pnas.79.11.3637]
Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre, M., Nuciforo, P. G., Bensimon, A., Maestro, R., Pelicci, P. G., d'Adda di Fagagna, F. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444: 638-642, 2006. [PubMed: 17136094] [Full Text: https://doi.org/10.1038/nature05327]
Eccles, M. R., Millow, L. J., Wilkins, R. J., Reeve, A. E. Harvey-ras allele deletion detected by in situ hybridization to Wilms' tumor chromosomes. Hum. Genet. 67: 190-192, 1984. [PubMed: 6086496] [Full Text: https://doi.org/10.1007/BF00272999]
Fasano, O., Aldrich, T., Tamanoi, F., Taparowsky, E., Furth, M., Wigler, M. Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc. Nat. Acad. Sci. 81: 4008-4012, 1984. [PubMed: 6330729] [Full Text: https://doi.org/10.1073/pnas.81.13.4008]
Fearon, E. R., Antonarakis, S. E., Meyers, D. A., Levine, M. A. c-Ha-ras-1 oncogene lies between beta-globin and insulin loci on human chromosome 11p. Am. J. Hum. Genet. 36: 329-337, 1984. [PubMed: 6324580]
Fearon, E. R., Feinberg, A. P., Hamilton, S. H., Vogelstein, B. Loss of genes on the short arm of chromosome 11 in bladder cancer. Nature 318: 377-380, 1985. [PubMed: 2999610] [Full Text: https://doi.org/10.1038/318377a0]
Feinberg, A. P., Vogelstein, B., Droller, M. J., Baylin, S. B., Nelkin, B. D. Mutation affecting the 12th amino acid of the C-Ha-ras oncogene product occurs infrequently in human cancer. Science 220: 1175-1177, 1983. [PubMed: 6304875] [Full Text: https://doi.org/10.1126/science.6304875]
Fisher, J. H., Miller, Y. E., Sparkes, R. S., Bateman, J. B., Kimmel, K. A., Carey, T. E., Rodell, T., Shoemaker, S. A., Scoggin, C. H. Wilms' tumor-aniridia association: segregation of affected chromosome in somatic cell hybrids, identification of cell surface antigen associated with deleted area, and regional mapping of c-Ha-ras-1 oncogene, insulin gene, and beta-globin gene. Somat. Cell Molec. Genet. 10: 455-464, 1984. [PubMed: 6089356] [Full Text: https://doi.org/10.1007/BF01534850]
Fujita, J., Srivastava, S. K., Kraus, M. H., Rhim, J. S., Tronick, S. R., Aaronson, S. A. Frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors. Proc. Nat. Acad. Sci. 82: 3849-3853, 1985. [PubMed: 2987950] [Full Text: https://doi.org/10.1073/pnas.82.11.3849]
Fujita, J., Yoshida, O., Yuasa, Y., Rhim, J. S., Hatanaka, M., Aaronson, S. A. Ha-ras oncogenes are activated by somatic alterations in human urinary tract tumours. Nature 309: 464-466, 1984. [PubMed: 6328318] [Full Text: https://doi.org/10.1038/309464a0]
Gerhard, D. S., Kidd, K. K., Housman, D., Gusella, J. F., Kidd, J. R. Data on the genetic map of the short arm of chromosome 11 (11p). (Abstract) Cytogenet. Cell Genet. 37: 478, 1984.
Gibbs, J. B., Ellis, R. W., Scolnick, E. M. Autophosphorylation of v-Ha-ras p21 is modulated by amino acid residue 12. Proc. Nat. Acad. Sci. 81: 2674-2678, 1984. [PubMed: 6609366] [Full Text: https://doi.org/10.1073/pnas.81.9.2674]
Goriely, A., Hansen, R. M. S., Taylor, I. B., Olesen, I. A., Jacobsen, G. K., McGowan, S. J., Pfeifer, S. P., McVean, G. A. T., Rajpert-De Meyts, E., Wilkie, A. O. M. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nature Genet. 41: 1247-1252, 2009. [PubMed: 19855393] [Full Text: https://doi.org/10.1038/ng.470]
Gough, D. J., Corlett, A., Schlessinger, K., Wegrzyn, J., Larner, A. C., Levy, D. E. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324: 1713-1716, 2009. [PubMed: 19556508] [Full Text: https://doi.org/10.1126/science.1171721]
Goyette, M., Petropoulos, C. J., Shank, P. R., Fausto, N. Expression of a cellular oncogene during liver regeneration. Science 219: 510-512, 1983. [PubMed: 6297003] [Full Text: https://doi.org/10.1126/science.6297003]
Greenhalgh, D. A., Kinsella, A. R. c-Ha-ras not c-Ki-ras activation in three colon tumour cell lines. Carcinogenesis 6: 1533-1535, 1985. [PubMed: 2994902] [Full Text: https://doi.org/10.1093/carcin/6.10.1533]
Gremer, L., De Luca, A., Merbitz-Zahradnik, T., Dallapiccola, B., Morlot, S., Tartaglia, M., Kutsche, K., Ahmadian, M. R., Rosenberger, G. Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation. Hum. Molec. Genet. 19: 790-802, 2010. [PubMed: 19995790] [Full Text: https://doi.org/10.1093/hmg/ddp548]
Gripp, K. W., Hopkins, E., Sol-Church, K., Stabley, D. L., Axelrad, M. E., Doyle, D., Dobyns, W. B., Hudson, C., Johnson, J., Tenconi, R., Graham, G. E., Sousa, A. B., Heller, R., Piccione, M., Corsello, G., Herman, G. E., Tartaglia, M., Lin, A. E. Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C. Am. J. Med. Genet. 155A: 706-716, 2011. [PubMed: 21438134] [Full Text: https://doi.org/10.1002/ajmg.a.33884]
Gripp, K. W., Innes, A. M., Axelrad, M. E., Gillan, T. L., Parboosingh, J. S., Davies, C., Leonard, N. J., Lapointe, M., Doyle, D., Catalano, S., Nicholson, L., Stabley, D. L., Sol-Church, K. Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? Am. J. Med. Genet. 146A: 683-690, 2008. [PubMed: 18247425] [Full Text: https://doi.org/10.1002/ajmg.a.32227]
Gripp, K. W., Lin, A. E., Stabley, D. L., Nicholson, L., Scott, C. I., Jr., Doyle, D., Aoki, Y., Matsubara, Y., Zackai, E. H., Lapunzina, P., Gonzalez-Meneses, A., Holbrook, J., Agresta, C. A., Gonzalez, I. L., Sol-Church, K. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am. J. Med. Genet. 140A: 1-7, 2006. [PubMed: 16329078] [Full Text: https://doi.org/10.1002/ajmg.a.31047]
Groesser, L., Herschberger, E., Ruetten, A., Ruivenkamp, C., Lopriore, E., Zutt, M., Langmann, T., Singer, S., Klingseisen, L., Schneider-Brachert, W., Toll, A., Real, F. X., Landthaler, M., Hafner, C. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nature Genet. 44: 783-787, 2012. [PubMed: 22683711] [Full Text: https://doi.org/10.1038/ng.2316]
Hafner, C., Toll, A., Gantner, S., Mauerer, A., Lurkin, I., Acquadro, F., Fernandez-Casado, A., Zwarthoff, E. C., Dietmaier, W., Baselga, E., Parera, E., Vicente, A., Casanova, A., Cigudosa, J., Mentzel, T., Pujol, R. M., Landthaler, M., Real, F. X. Keratinocytic epidermal nevi are associated with mosaic RAS mutations. J. Med. Genet. 49: 249-253, 2012. [PubMed: 22499344] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100637]
Hafner, C., Toll, A., Real, F. X. HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. (Letter) New Eng. J. Med. 365: 1940-1942, 2011. [PubMed: 22087699] [Full Text: https://doi.org/10.1056/NEJMc1109381]
Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., Weinberg, R. A. Creation of human tumour cells with defined genetic elements. Nature 400: 464-468, 1999. [PubMed: 10440377] [Full Text: https://doi.org/10.1038/22780]
Hiwasa, T., Sakiyama, S., Yokoyama, S., Ha, J.-M., Fujita, J., Noguchi, S., Bando, Y., Kominami, E., Katunuma, N. Inhibition of cathepsin L-induced degradation of epidermal growth factor receptors by c-Ha-ras gene products. Biochem. Biophys. Res. Commun. 151: 78-85, 1988. [PubMed: 3279952] [Full Text: https://doi.org/10.1016/0006-291x(88)90561-x]
Howe, G. A., Kazda, K., Addison, C. L. MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2. PLoS One 12: e0185619, 2017. Note: Electronic Article. [PubMed: 28977001] [Full Text: https://doi.org/10.1371/journal.pone.0185619]
Huerre, C., Despoisse, S., Gilgenkrantz, S., Lenoir, G. M., Junien, C. c-Ha-ras1 is not deleted in aniridia-Wilms' tumour association. Nature 305: 638-641, 1983. [PubMed: 6312328] [Full Text: https://doi.org/10.1038/305638a0]
Ishii, S., Merlino, G. T., Pastan, I. Promoter region of the human Harvey ras proto-oncogene: similarity to the EGF receptor proto-oncogene promoter. Science 230: 1378-1381, 1985. [PubMed: 2999983] [Full Text: https://doi.org/10.1126/science.2999983]
Jhanwar, S. C., Neel, B. G., Hayward, W. S., Chaganti, R. S. K. Localization of c-ras oncogene family on human germ-line chromosomes. Proc. Nat. Acad. Sci. 80: 4794-4797, 1983. [PubMed: 6308650] [Full Text: https://doi.org/10.1073/pnas.80.15.4794]
Johnson, S. M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Reinert, K. L., Brown, D., Slack, F. J. RAS is regulated by the let-7 microRNA family. Cell 120: 635-647, 2005. [PubMed: 15766527] [Full Text: https://doi.org/10.1016/j.cell.2005.01.014]
Junien, C., Huerre, C., Despoisse, S., Gilgenkrantz, S., Lenoir, G. M. c-Ha-ras1 is not deleted in del(11p13) Wilms' tumor (WAGR) and maps to 11p15.1-11p15.5. (Abstract) Cytogenet. Cell Genet. 37: 503, 1984.
Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O. B., O'Sullivan, J., De Sandre-Giovannoli, A., Reardon, W., and 14 others. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J. Med. Genet. 43: 401-405, 2006. [PubMed: 16443854] [Full Text: https://doi.org/10.1136/jmg.2005.040352]
Krontiris, T. G., Devlin, B., Karp, D. D., Robert, N. J., Risch, N. An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. New Eng. J. Med. 329: 517-523, 1993. [PubMed: 8336750] [Full Text: https://doi.org/10.1056/NEJM199308193290801]
Krontiris, T. G., DiMartino, N. A., Colb, M., Parkinson, D. R. Unique allelic restriction fragments of the human Ha-ras locus in leukocyte and tumour DNAs of cancer patients. Nature 313: 369-374, 1985. [PubMed: 2578622] [Full Text: https://doi.org/10.1038/313369a0]
Kuniba, H., Pooh, R. K., Sasaki, K., Shimokawa, O., Harada, N., Kondoh, T., Egashira, M., Moriuchi, H., Yoshiura, K., Niikawa, N. Prenatal diagnosis of Costello syndrome using 3D ultrasonography amniocentesis confirmation of the rare HRAS mutation G12D. (Letter) Am. J. Med. Genet. 149A: 785-787, 2009. [PubMed: 18642361] [Full Text: https://doi.org/10.1002/ajmg.a.32335]
Levinsohn, J. L., Teng, J., Craiglow, B. G., Loring, E. C., Burrow, T. A., Mane, S. S., Overton, J. D., Lifton, R. P., McNiff, J. M., Lucky, A. W., Choate, K. A. Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi. (Letter) J. Invest. Derm. 134: 1149-1152, 2014. [PubMed: 24129065] [Full Text: https://doi.org/10.1038/jid.2013.430]
Lim, Y. H., Ovejero, D., Sugarman, J. S., DeKlotz, C. M. C., Maruri, A., Eichenfield, L. F., Kelley, P. K., Juppner, H., Gottschalk, M., Tifft, C. J., Gafni, R. I., Boyce, A. M., and 12 others. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum. Molec. Genet. 23: 397-407, 2014. [PubMed: 24006476] [Full Text: https://doi.org/10.1093/hmg/ddt429]
Lo, I. F. M., Brewer, C., Shannon, N., Shorto, J., Tang, B., Black, G., Soo, M. T., Ng, D. K. K., Lam, S. T. S., Kerr, B. Severe neonatal manifestations of Costello syndrome. (Letter) J. Med. Genet. 45: 167-171, 2008. [PubMed: 18039947] [Full Text: https://doi.org/10.1136/jmg.2007.054411]
Lorenz, S., Lissewski, C., Simsek-Kiper, P. O., Alanay, Y., Boduroglu, K., Zenker, M., Rosenberger, G. Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome. Hum. Molec. Genet. 22: 1643-1653, 2013. [PubMed: 23335589] [Full Text: https://doi.org/10.1093/hmg/ddt014]
Lu, C.-W., Yabuuchi, A., Chen, L., Viswanathan, S., Kim, K., Daley, G. Q. Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos. Nature Genet. 40: 921-926, 2008. [PubMed: 18536715] [Full Text: https://doi.org/10.1038/ng.173]
Matallanas, D., Arozarena, I., Berciano, M. T., Aaronson, D. S., Pellicer, A., Lafarga, M., Crespo, P. Differences on the inhibitory specificities of H-Ras, K-Ras, and N-Ras (N17) dominant negative mutants are related to their membrane microlocalization. J. Biol. Chem. 278: 4572-4581, 2003. [PubMed: 12458225] [Full Text: https://doi.org/10.1074/jbc.M209807200]
McMurray, H. R., Sampson, E. R., Compitello, G., Kinsey, C., Newman, L., Smith, B., Chen, S.-R., Klebanov, L., Salzman, P., Yakovlev, A., Land, H. Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype. Nature 453: 1112-1116, 2008. [PubMed: 18500333] [Full Text: https://doi.org/10.1038/nature06973]
Mochizuki, N., Yamashita, S., Kurokawa, K., Ohba, Y., Nagai, T., Miyawaki, A., Matsuda, M. Spatio-temporal images of growth-factor-induced activation of Ras and Rap1. Nature 411: 1065-1068, 2001. [PubMed: 11429608] [Full Text: https://doi.org/10.1038/35082594]
Muschel, R. J., Khoury, G., Lebowitz, P., Koller, R., Dhar, R. The human c-ras1(H) oncogene: a mutation in normal and neoplastic tissue from the same patient. Science 219: 853-856, 1983. Note: Retraction: Science 220: 336 only, 1983. [PubMed: 6337398] [Full Text: https://doi.org/10.1126/science.6337398]
Newbold, R. F., Overell, R. W. Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature 304: 648-651, 1983. [PubMed: 6877385] [Full Text: https://doi.org/10.1038/304648a0]
Nikiforova, M. N., Lynch, R. A., Biddinger, P. W., Alexander, E. K., Dorn, G. W., II, Tallini, G., Kroll, T. G., Nikiforov, Y. E. RAS point mutations and PAX8-PPAR-gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J. Clin. Endocr. Metab. 88: 2318-2326, 2003. [PubMed: 12727991] [Full Text: https://doi.org/10.1210/jc.2002-021907]
Oft, M., Akhurst, R. J., Balmain, A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nature Cell Biol. 4: 487-494, 2002. [PubMed: 12105419] [Full Text: https://doi.org/10.1038/ncb807]
Phelan, C. M., Rebbeck, T. R., Weber, B. L., Devilee, P., Ruttledge, M. H., Lynch, H. T., Lenoir, G. M., Stratton, M. R., Easton, D. F., Ponder, B. A. J., Cannon-Albright, L., Larsson, C., Goldgar, D. E., Narod, S. A. Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nature Genet. 12: 309-311, 1996. [PubMed: 8589723] [Full Text: https://doi.org/10.1038/ng0396-309]
Piccione, M., Piro, E., Pomponi, M. G., Matina, F., Pietrobono, R., Candela, E., Gabriele, B., Neri, G., Corsello, G. A premature infant with Costello syndrome due to a rare G13C HRAS mutation. Am. J. Med. Genet. 149A: 487-489, 2009. [PubMed: 19213030] [Full Text: https://doi.org/10.1002/ajmg.a.32674]
Pincus, M. R., van Renswoude, J., Harford, J. B., Chang, E. H., Carty, R. P., Klausner, R. D. Prediction of the three-dimensional structure of the transforming region of the EJ/T24 human bladder oncogene product and its normal cellular homologue. Proc. Nat. Acad. Sci. 80: 5253-5257, 1983. [PubMed: 6577419] [Full Text: https://doi.org/10.1073/pnas.80.17.5253]
Popescu, N. C., Amsbaugh, S. C., DiPaolo, J. A., Tronick, S. R., Aaronson, S. A., Swan, D. C. Chromosomal localization of three human ras genes by in situ molecular hybridization. Somat. Cell Molec. Genet. 11: 149-155, 1985. [PubMed: 3856955] [Full Text: https://doi.org/10.1007/BF01534703]
Rocks, O., Peyker, A., Kahms, M., Verveer, P. J., Koerner, C., Lumbierres, M., Kuhlmann, J., Waldmann, H., Wittinghofer, A., Bastiaens, P. I. H. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307: 1746-1752, 2005. [PubMed: 15705808] [Full Text: https://doi.org/10.1126/science.1105654]
Russell, M. W., Munroe, D. J., Bric, E., Housman, D. E., Dietz-Band, J., Riethman, H. C., Collins, F. S., Brody, L. C. A 500-kb physical map and contig from the Harvey ras-1 gene to the 11p telomere. Genomics 35: 353-360, 1996. [PubMed: 8661149] [Full Text: https://doi.org/10.1006/geno.1996.0367]
Ryberg, D., Tefre, T., Ovrebo, S., Skaug, V., Stangeland, L., Naalsund, A., Baera, R., Borresen, A.-L., Haugen, A. Ha-ras-1 alleles in Norwegian lung cancer patients. Hum. Genet. 86: 40-44, 1990. [PubMed: 1979305] [Full Text: https://doi.org/10.1007/BF00205169]
Sarin, K. Y., McNiff, J. M., Kwok, S., Kim, J., Khavari, P. A. Activating HRAS mutation in nevus spilus. (Letter) J. Invest. Derm. 134: 1766-1768, 2014. [PubMed: 24390138] [Full Text: https://doi.org/10.1038/jid.2014.6]
Sarin, K. Y., Sun, B. K., Bangs, C. D., Cherry, A., Swetter, S. M., Kim, J., Khavari, P. A. Activating HRAS mutation in agminated Spitz nevi arising in a nevus spilus. JAMA Derm. 149: 1077-1080, 2013. [PubMed: 23884457] [Full Text: https://doi.org/10.1001/jamadermatol.2013.4745]
Schuhmacher, A. J., Guerra, C., Sauzeau, V., Canamero, M., Bustelo, X. R., Barbacid, M. A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. J. Clin. Invest. 118: 2169-2179, 2008. [PubMed: 18483625] [Full Text: https://doi.org/10.1172/JCI34385]
Sears, R., Leone, G., DeGregori, J., Nevins, J. R. Ras enhances Myc protein stability. Molec. Cell 3: 169-179, 1999. [PubMed: 10078200] [Full Text: https://doi.org/10.1016/s1097-2765(00)80308-1]
Seeburg, P. H., Colby, W. W., Capon, D. J., Goeddel, D. V., Levinson, A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312: 71-75, 1984. [PubMed: 6092966] [Full Text: https://doi.org/10.1038/312071a0]
Sekiya, T., Fushimi, M., Hori, H., Hirohashi, S., Nishimura, S., Sugimura, T. Molecular cloning and the total nucleotide sequence of the human c-Ha-ras-1 gene activated in a melanoma from a Japanese patient. Proc. Nat. Acad. Sci. 81: 4771-4775, 1984. [PubMed: 6087347] [Full Text: https://doi.org/10.1073/pnas.81.15.4771]
Selcen, D., Kupsky, W. J., Benjamins, D., Nigro, M. A. Myopathy with muscle spindle excess: a new congenital neuromuscular syndrome? Muscle Nerve 24: 138-143, 2001. Note: Erratum: Muscle Nerve 24: 445 only, 2001. [PubMed: 11150980] [Full Text: https://doi.org/10.1002/1097-4598(200101)24:1<138::aid-mus22>3.0.co;2-3]
Sol-Church, K., Stabley, D. L., Nicholson, L., Gonzalez, I. L., Gripp, K. W. Paternal bias in parental origin of HRAS mutations in Costello syndrome. Hum. Mutat. 27: 736-741, 2006. [PubMed: 16835863] [Full Text: https://doi.org/10.1002/humu.20381]
Srivastava, S. K., Yuasa, Y., Reynolds, S. H., Aaronson, S. A. Effects of two major activating lesions on the structure and conformation of human ras oncogene products. Proc. Nat. Acad. Sci. 82: 38-42, 1985. [PubMed: 3918304] [Full Text: https://doi.org/10.1073/pnas.82.1.38]
Stallings, R. L., Crawford, B. D., Black, R. J., Chang, E. H. Assignment of RAS proto-oncogenes in Chinese hamsters: implications for mammalian gene linkage conservation and neoplasia. Cytogenet. Cell Genet. 43: 2-5, 1986. [PubMed: 3022995] [Full Text: https://doi.org/10.1159/000132289]
Stassou, S., Nadroo, A., Schubert, R., Chin, S., Gudavalli, M. A new syndrome of myopathy with muscle spindle excess. J. Perinat. Med. 33: 179-182, 2005. [PubMed: 15843272] [Full Text: https://doi.org/10.1515/JPM.2005.034]
Stites, E. C., Trampont, P. C., Ma, Z., Ravichandran, K. S. Network analysis of oncogenic Ras activation in cancer. Science 318: 463-467, 2007. [PubMed: 17947584] [Full Text: https://doi.org/10.1126/science.1144642]
Taparowsky, E., Suard, Y., Fasano, O., Shimizu, K., Goldfarb, M., Wigler, M. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300: 762-765, 1982. [PubMed: 7177195] [Full Text: https://doi.org/10.1038/300762a0]
To, M. D., Wong, C. E., Karnezis, A. N., Del Rosario, R., Di Lauro, R., Balmain, A. Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nature Genet. 40: 1240-1244, 2008. [PubMed: 18758463] [Full Text: https://doi.org/10.1038/ng.211]
Tong, L., de Vos, A. M., Milburn, M. V., Jancarik, J., Noguchi, S., Nishimura, S., Miura, K., Ohtsuka, E., Kim, S.-H. Structural differences between a RAS oncogene protein and the normal protein. Nature 337: 90-93, 1989. [PubMed: 2642607] [Full Text: https://doi.org/10.1038/337090a0]
van der Burgt, I., Kupsky, W., Stassou, S., Nadroo, A., Barroso, C., Diem, A., Kratz, C. P., Dvorsky, R., Ahmadian, M. R., Zenker, M. Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. (Letter) J. Med. Genet. 44: 459-462, 2007. [PubMed: 17412879] [Full Text: https://doi.org/10.1136/jmg.2007.049270]
Vasko, V., Ferrand, M., Di Cristofaro, J., Carayon, P., Henry, J. F., De Micco, C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J. Clin. Endocr. Metab. 88: 2745-2752, 2003. [PubMed: 12788883] [Full Text: https://doi.org/10.1210/jc.2002-021186]
Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S. M., Zlobin, A., Osborne, B. A., Gottipati, S., Aster, J. C., Hahn, W. C., Rudolf, M., Siziopikou, K., Kast, W. M., Miele, L. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Med. 8: 979-986, 2002. [PubMed: 12185362] [Full Text: https://doi.org/10.1038/nm754]
Wong-Staal, F., Dalla-Favera, R., Franchini, G., Gelmann, E. P., Gallo, R. C. Three distinct genes in human DNA related to the transforming genes of mammalian sarcoma retroviruses. Science 213: 226-228, 1981. [PubMed: 6264598] [Full Text: https://doi.org/10.1126/science.6264598]
Yokota, J., Tsunetsugu-Yokota, Y., Battifora, H., Le Fevre, C., Cline, M. J. Alterations of myc, myb, and ras(Ha) proto-oncogenes in cancers are frequent and show clinical correlation. Science 231: 261-265, 1986. [PubMed: 3941898] [Full Text: https://doi.org/10.1126/science.3941898]
Zampino, G., Pantaleoni, F., Carta, C., Cobellis, G., Vasta, I., Neri, C., Pogna, E. A., De Feo, E., Delogu, A., Sarkozy, A., Atzeri, F., Selicorni, A., Rauen, K. A., Cytrynbaum, C. S., Weksberg, R., Dallapiccola, B., Ballabio, A., Gelb, B. D., Neri, G., Tartaglia, M. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum. Mutat. 28: 265-272, 2007. [PubMed: 17054105] [Full Text: https://doi.org/10.1002/humu.20431]
Zhang, X., Kim, J., Ruthazer, R., McDevitt, M. A., Wazer, D. E., Paulson, K. E., Yee, A. S. The HBP1 transcriptional repressor participates in RAS-induced premature senescence. Molec. Cell. Biol. 26: 8252-8266, 2006. [PubMed: 16966377] [Full Text: https://doi.org/10.1128/MCB.00604-06]
Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L., Malinow, R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110: 443-455, 2002. [PubMed: 12202034] [Full Text: https://doi.org/10.1016/s0092-8674(02)00897-8]
Zutt, M., Strutz, F., Happle, R., Habenicht, E. M., Emmert, S., Haenssle, H. A., Kretschmer, L., Neumann, C. Schimmelpenning-Feuerstein-Mims syndrome with hypophosphatemic rickets. Dermatology 207: 72-76, 2003. [PubMed: 12835555] [Full Text: https://doi.org/10.1159/000070948]