Alternative titles; symbols
HGNC Approved Gene Symbol: RIT1
Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:155,897,808-155,911,349 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q22 | Noonan syndrome 8 | 615355 | Autosomal dominant | 3 |
RIT belongs to the RAS (HRAS; 190020) subfamily of small GTPases (Hynds et al., 2003).
By PCR using degenerate primers based on the conserved G3 and G4 domains of RAS, followed by screening a mouse retina cDNA library, Lee et al. (1996) cloned mouse Rit. The deduced 219-amino acid protein has a calculated molecular mass of 25.6 kD. By EST database analysis, Lee et al. (1996) identified human RIT. The deduced human protein contains 219 amino acids and shares 94% identity with mouse Rit. Human and mouse RIT have 5 highly conserved domains characteristic of small G proteins, but they lack the C-terminal CAAX prenylation motif found in several other RAS-like proteins. Northern blot analysis detected a 1.2-kb transcript in all mouse tissues examined. Epitope-tagged mouse Rit localized to the plasma membrane of transfected cells.
By searching an EST database for sequences similar to Drosophila Ric, Wes et al. (1996) identified human RIT and RIN (609592). The core GTPase domain of RIT shares 76% identity with that of RIN, and there is only 1 conservative substitution between the 2 human proteins and Drosophila Ric within the effector G2 region. Northern blot analysis detected RIT transcripts of 1.35, 2.9, and 3.9 kb in most tissues examined.
Lee et al. (1996) demonstrated that mouse Rit bound radiolabeled GTP.
Shao et al. (1999) demonstrated that recombinant human RIT and RIN bound GTP and exhibited intrinsic GTPase activity. Conversion of gln79 to leu in RIT resulted in complete loss of GTPase activity. The activity of RIT and RIN was significantly different from that of the majority of RAS-related GTPases, and the GTP dissociation rates were 5- to 10-fold faster than most RAS-like GTPases. Yeast 2-hybrid analysis showed that RIT and RIN interacted with the RAS-binding proteins RALGDS (601619), RLF (180610), and AF6 (MLLT4; 159559), but not with RAF kinases (e.g., RAF1; 164760), RIN1 (605965), or the p110 subunit of PI3K (see 171834). Shao et al. (1999) concluded that RIT and RIN regulate signaling pathways and cellular processes distinct from those controlled by RAS.
By expression of RIT in a human neuroblastoma cell line, Hynds et al. (2003) demonstrated that RIT increased neurite outgrowth and branching through MEK (see MEK1; 176872)-dependent and MEK-independent signaling mechanisms, respectively. Adenoviral expression of wildtype or constitutively active RIT increased neurite initiation, elongation, and branching on endogenous matrix or a purified laminin-1 substratum. This outgrowth was morphologically distinct from that promoted by constitutively active RAS or RAF. Constitutively active RIT increased phosphorylation of ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948), but not AKT (see AKT1; 164730). A MEK inhibitor blocked RIT-induced neurite initiation, but not elongation or branching.
Shi and Andres (2005) found that stimulation of a rat pheochromocytoma cell line by growth factors, including nerve growth factor (NGF; 162030), resulted in rapid and prolonged Rit activation. Ectopic expression of active human RIT promoted neurite outgrowth and stimulated activation of both Erk and p38 MAP kinase (MAPK14; 600289) signaling pathways. RIT-induced differentiation depended upon both MAP kinase cascades, since MEK inhibition blocked RIT-induced neurite outgrowth, and p38 blockade inhibited neurite elongation and branching, but not neurite initiation. Moreover, the ability of NGF to promote neuronal differentiation was attenuated by Rit knockdown.
Heo et al. (2006) surveyed plasma membrane targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Of 48 proteins that were localized to the plasma membrane, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate lipids, Heo et al. (2006) developed a chemical phosphatase activation method to deplete plasma membrane phosphatidylinositol 4,5-bisphosphate. Unexpectedly, proteins with polybasic clusters dissociated from the plasma membrane only when both phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were depleted, arguing that both lipid second messengers jointly regulate plasma membrane targeting.
Wes et al. (1996) stated that the RIT gene was mapped to chromosome 1 by somatic cell hybrid analysis. The mouse Rit gene maps to chromosome 3.
In 17 unrelated patients with Noonan syndrome-8 (NS8; 615355), Aoki et al. (2013) identified heterozygous mutations in the RIT1 gene (see, e.g., 609591.0001-609591.0004). The first mutations were found by exome sequencing and subsequent mutations were identified from a larger cohort of patients screened for the RIT1 gene. A total of 9 missense mutations were found in 17 (9%) of 180 individuals suspected to have the disorder. The phenotype was characterized by short stature, distinctive facial features, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. A subset of patients showed intellectual disabilities. All of the mutations occurred de novo, except in 1 patient who inherited the mutation from a mother with a Noonan syndrome phenotype. The mutations tended to cluster in the switch II region, and in vitro functional expression studies of 3 of the mutations showed that they resulted in a gain of function. Transfection of 2 of the mutations into zebrafish embryos resulted in a variety of developmental defects, including gastrulation defects, craniofacial abnormalities, pericardial edema, and elongated yolk sac. A smaller percentage of mutant embryos showed even more disorganized growth and abnormal cardiogenesis. The findings were similar to those observed with mutations in other RAS genes (see, e.g., PTPN11, 176876; SOS1, 182530; NRAS, 164790) causing other forms of Noonan syndrome.
In 6 Brazilian patients with Noonan syndrome but without mutation in selected exons of any known Noonan syndrome-causing genes, Bertola et al. (2014) identified 4 heterozygous missense mutations in the RIT1 gene, all of which had previously been identified in patients with NS8 by Aoki et al. (2013). The mutations were identified by exome sequencing. Parental DNA, which was available for only 2 patients, showed that the mutations were probably de novo. The affected patients had a high frequency of high birthweight, relative macrocephaly, left ventricular hypertrophy, and ectodermal findings such as curly hair, hyperpigmentation, and wrinkled palms and soles. There was no apparent intellectual disability, but formal testing was not performed. Other findings were similar to those observed with mutations in genes causing different forms of Noonan syndrome. Bertola et al. (2014) suggested possible hotspots at residues 57 and 95 of the protein due to recurrent mutations, and recommended that RIT1 be added to gene panels for the molecular diagnosis of Noonan syndrome.
In 4 unrelated Polish girls with NS8, Gos et al. (2014) identified 3 different heterozygous missense mutations in the RIT1 gene (609591.0004-609591.0006). The mutations in the first 2 patients were found by whole-exome sequencing after mutations in common Noonan syndrome genes were excluded. The mutations in the second 2 patients were found by direct sequencing of the RIT1 gene in 64 patients with Noonan syndrome. Functional studies of the variants were not performed. The RIT1 mutation rate in this study was estimated at 3.8% (4 of 106 NS patients).
Kouz et al. (2016) sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Eleven different RIT1 missense mutations, 3 of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. RIT1 is 1 of the 4 most common genes mutated in Noonan syndrome.
Castel et al. (2019) used an isogenic germline knockin mouse model to study the effects of RIT1 mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, Castel et al. (2019) detected a RIT1 interactor, LZTR1 (600574), that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. Castel et al. (2019) concluded that their results highlighted a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1.
In 4 unrelated patients with Noonan syndrome-8 (NS8; 615355), Aoki et al. (2013) identified a de novo heterozygous c.170C-G transversion in exon 4 of the RIT1 gene, resulting in an ala57-to-gly (A57G) substitution at a conserved residue. In vitro cellular expression studies showed that the A57G mutation resulted in a gain of function.
In 2 unrelated Brazilian patients with NS8, Bertola et al. (2014) identified heterozygosity for the A57G mutation.
In a patient with Noonan syndrome-8 (NS8; 615355), Aoki et al. (2013) identified a de novo heterozygous c.242A-G transition in exon 5 of the RIT1 gene, resulting in a glu81-to-gly (E81G) substitution at a conserved residue. In vitro cellular expression studies showed that the E81G mutation resulted in a gain of function. Transfection of the E81G mutation into zebrafish embryos resulted in a variety of developmental defects, including gastrulation defects, craniofacial abnormalities, pericardial edema, and elongated yolk sac. A smaller percentage of mutant embryos showed even more disorganized growth and abnormal cardiogenesis.
In 2 unrelated patients with Noonan syndrome-8 (NS8; 615355), Aoki et al. (2013) identified a de novo heterozygous c.246T-G transversion in exon 5 of the RIT1 gene, resulting in a phe82-to-leu (F82L) substitution at a conserved residue. The mutation, which was initially found by exome sequencing, was not present in several control databases. In vitro cellular expression studies showed that the F82L mutation resulted in a gain of function.
In 4 unrelated patients with Noonan syndrome-8 (NS8; 615355), Aoki et al. (2013) identified a de novo heterozygous c.284G-C transversion in exon 5 of the RIT1 gene, resulting in a gly95-to-ala (G95A) substitution. The mutation, which was initially found by exome sequencing, was not present in several control databases. In vitro cellular expression studies showed that the G95A mutation resulted in a gain of function. Transfection of the G95A mutation into zebrafish embryos resulted in a variety of developmental defects, including gastrulation defects, craniofacial abnormalities, pericardial edema, and elongated yolk sac. A smaller percentage of mutant embryos showed even more disorganized growth and abnormal cardiogenesis.
In 2 unrelated Brazilian patients with NS8, Bertola et al. (2014) identified heterozygosity for the G95A mutation.
Gos et al. (2014) identified a heterozygous G95A mutation in 2 unrelated Polish girls with NS8.
In a 6-year-old Polish girl with Noonan syndrome-8 (NS8; 615355), Gos et al. (2014) identified a de novo heterozygous c.244T-G transversion (c.244T-G, NM_006912) in the RIT1 gene, resulting in a phe82-to-val (F82V) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed. A different mutation at the same codon has been reported (F82L; 609591.0003).
In a 5.5-year-old Polish girl with Noonan syndrome-8 (NS8; 615355), Gos et al. (2014) identified a de novo heterozygous c.270G-C transversion (c.270G-C, NM_006912) in the RIT1 gene, resulting in a met90-to-ile (M90I) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed.
Aoki, Y., Niihori, T., Banjo, T., Okamoto, N., Mizuno, S., Kurosawa, K., Ogata, T., Takada, F., Yano, M., Ando, T., Hoshika, T., Barnett, C., and 13 others. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 93: 173-180, 2013. [PubMed: 23791108] [Full Text: https://doi.org/10.1016/j.ajhg.2013.05.021]
Bertola, D. R., Yamamoto, G. L., Almeida, T. F., Buscarilli, M., Jorge, A. A. L., Malaquias, A. C., Kim, C. A., Takahashi, V. N. V., Passos-Bueno, M. R., Pereira, A. C. Further evidence of the importance of RIT1 in Noonan syndrome. Am. J. Med. Genet. 164A: 2952-2957, 2014. [PubMed: 25124994] [Full Text: https://doi.org/10.1002/ajmg.a.36722]
Castel, P., Cheng, A., Cuevas-Navarro, A., Everman, D. B., Papageorge, A. G., Simanshu, D. K., Tankka, A., Galeas, J., Urisman, A., McCormick, F. RIT1 oncoproteins escape LZTR1-mediated proteolysis. Science 363: 1226-1230, 2019. [PubMed: 30872527] [Full Text: https://doi.org/10.1126/science.aav1444]
Gos, M., Fahiminiya, S., Poznanski, J., Klapecki, J., Obersztyn, E., Piotrowicz, M., Wierzba, J., Posmyk, R., Bal, J., Majewski, J. Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity. Am. J. Med. Genet. 164A: 2310-2316, 2014. [PubMed: 24939608] [Full Text: https://doi.org/10.1002/ajmg.a.36646]
Heo, W. D., Inoue, T., Park, W. S., Kim, M. L., Park, B. O., Wandless, T. J., Meyer, T. PI(3,4,5)P(3) and PI(4,5)P(2) lipids target proteins with polybasic clusters to the plasma membrane. Science 314: 1458-1461, 2006. [PubMed: 17095657] [Full Text: https://doi.org/10.1126/science.1134389]
Hynds, D. L., Spencer, M. L., Andres, D. A., Snow, D. M. Rit promotes MEK-independent neurite branching in human neuroblastoma cells. J. Cell Sci. 116: 1925-1935, 2003. [PubMed: 12668729] [Full Text: https://doi.org/10.1242/jcs.00401]
Kouz, K., Lissewski, C., Spranger, S., Mitter, D., Riess, A., Lopez-Gonzalez, V., Luttgen, S., Aydin, H., von Deimling, F., Evers, C., Hahn, A., Hempel, M., and 14 others. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. Genet. Med. 18: 1226-1234, 2016. [PubMed: 27101134] [Full Text: https://doi.org/10.1038/gim.2016.32]
Lee, C.-H. J., Della, N. G., Chew, C. E., Zack, D. J. Rin, a neuron-specific and calmodulin-binding small G-protein, and Rit define a novel subfamily of Ras proteins. J. Neurosci. 16: 6784-6794, 1996. [PubMed: 8824319] [Full Text: https://doi.org/10.1523/JNEUROSCI.16-21-06784.1996]
Shao, H., Kadono-Okuda, K., Finlin, B. S., Andres, D. A. Biochemical characterization of the Ras-related GTPases Rit and Rin. Arch. Biochem. Biophys. 371: 207-219, 1999. [PubMed: 10545207] [Full Text: https://doi.org/10.1006/abbi.1999.1448]
Shi, G.-X., Andres, D. A. Rit contributes to nerve growth factor-induced neuronal differentiation via activation of B-Raf-extracellular signal-regulated kinase and p38 mitogen-activated protein kinase cascades. Molec. Cell. Biol. 25: 830-846, 2005. [PubMed: 15632082] [Full Text: https://doi.org/10.1128/MCB.25.2.830-846.2005]
Wes, P. D., Yu, M., Montell, C. RIC, a calmodulin-binding Ras-like GTPase. EMBO J. 15: 5839-5848, 1996. [PubMed: 8918462]