Full text data of RIT1
RIT1
(RIBB, RIT, ROC1)
[Confidence: low (only semi-automatic identification from reviews)]
GTP-binding protein Rit1 (Ras-like protein expressed in many tissues; Ras-like without CAAX protein 1)
GTP-binding protein Rit1 (Ras-like protein expressed in many tissues; Ras-like without CAAX protein 1)
UniProt
Q92963
ID RIT1_HUMAN Reviewed; 219 AA.
AC Q92963; B4DQE8; O00646; O00720; Q5VY89; Q5VY90;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1997, sequence version 1.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=GTP-binding protein Rit1;
DE AltName: Full=Ras-like protein expressed in many tissues;
DE AltName: Full=Ras-like without CAAX protein 1;
GN Name=RIT1; Synonyms=RIBB, RIT, ROC1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8824319;
RA Lee C.H.J., Della N.G., Chew C.E., Zack D.J.;
RT "Rin, a neuron-specific and calmodulin-binding small G-protein, and
RT Rit define a novel subfamily of ras proteins.";
RL J. Neurosci. 16:6784-6794(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8918462;
RA Wes P.D., Yu M., Montell C.;
RT "RIC, a calmodulin-binding Ras-like GTPase.";
RL EMBO J. 15:5839-5848(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Kawasaki H., Housman D.E., Graybiel A.M.;
RT "Characterization of new small G proteins in the Ras subfamily.";
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION, INTERACTION
RP WITH MLLT4; RALGDS AND RLF, AND MUTAGENESIS OF SER-35; THR-53; GLU-55
RP AND GLN-79.
RC TISSUE=Retina;
RX PubMed=10545207; DOI=10.1006/abbi.1999.1448;
RA Shao H., Kadono-Okuda K., Finlin B.S., Andres D.A.;
RT "Biochemical characterization of the Ras-related GTPases Rit and
RT Rin.";
RL Arch. Biochem. Biophys. 371:207-219(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Esophagus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP FUNCTION, AND INTERACTION WITH BRAF AND RAF1.
RX PubMed=15632082; DOI=10.1128/MCB.25.2.830-846.2005;
RA Shi G.-X., Andres D.A.;
RT "Rit contributes to nerve growth factor-induced neuronal
RT differentiation via activation of B-Raf-extracellular signal-regulated
RT kinase and p38 mitogen-activated protein kinase cascades.";
RL Mol. Cell. Biol. 25:830-846(2005).
RN [12]
RP FUNCTION, VARIANTS NS8 GLY-57; GLY-81; LEU-82 AND ALA-95,
RP CHARACTERIZATION OF VARIANTS NS8 GLY-57; GLY-81; LEU-82 AND ALA-95,
RP AND VARIANTS THR-35; VAL-82; PRO-83 HIS-89 AND ILE-90.
RX PubMed=23791108; DOI=10.1016/j.ajhg.2013.05.021;
RA Aoki Y., Niihori T., Banjo T., Okamoto N., Mizuno S., Kurosawa K.,
RA Ogata T., Takada F., Yano M., Ando T., Hoshika T., Barnett C.,
RA Ohashi H., Kawame H., Hasegawa T., Okutani T., Nagashima T.,
RA Hasegawa S., Funayama R., Nagashima T., Nakayama K., Inoue S.,
RA Watanabe Y., Ogura T., Matsubara Y.;
RT "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK
RT pathway syndrome.";
RL Am. J. Hum. Genet. 93:173-180(2013).
CC -!- FUNCTION: Plays a crucial role in coupling NGF stimulation to the
CC activation of both EPHB2 and MAPK14 signaling pathways and in NGF-
CC dependent neuronal differentiation. Involved in ELK1
CC transactivation through the Ras-MAPK signaling cascade that
CC mediates a wide variety of cellular functions, including cell
CC proliferation, survival, and differentiation.
CC -!- ENZYME REGULATION: Alternates between an inactive form bound to
CC GDP and an active form bound to GTP.
CC -!- SUBUNIT: Interacts with MLLT4, the C-terminal domain of RALGDS and
CC RLF, but not with RIN1 and PIK3CA. RLF binds exclusively to the
CC active GTP-bound form. Strongly interacts with BRAF, but only
CC weakly with RAF1. BARF and RAF1 association is dependent upon the
CC GTP-bound state. Interacts with RGL3 (By similarity).
CC -!- INTERACTION:
CC Q13129:RLF; NbExp=3; IntAct=EBI-365845, EBI-958266;
CC -!- SUBCELLULAR LOCATION: Cell membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q92963-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92963-2; Sequence=VSP_045306;
CC Name=3;
CC IsoId=Q92963-3; Sequence=VSP_047114;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in many tissues.
CC -!- DISEASE: Noonan syndrome 8 (NS8) [MIM:615355]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial
CC dysmorphic features such as hypertelorism, a downward eyeslant and
CC low-set posteriorly rotated ears, and a high incidence of
CC congenital heart defects and hypertrophic cardiomyopathy. Other
CC features can include a short neck with webbing or redundancy of
CC skin, deafness, motor delay, variable intellectual deficits,
CC multiple skeletal defects, cryptorchidism, and bleeding diathesis.
CC Individuals with Noonan syndrome are at risk of juvenile
CC myelomonocytic leukemia, a myeloproliferative disorder
CC characterized by excessive production of myelomonocytic cells.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: Stimulation of the NGF and EGF receptor signaling
CC pathways results in rapid and prolonged activation.
CC -!- MISCELLANEOUS: Shows rapid uncatalyzed guanine nucleotide
CC dissociation rates, which are much faster than those of most Ras
CC subfamily members.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
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DR EMBL; U71203; AAB42213.1; -; mRNA.
DR EMBL; Y07566; CAA68851.1; -; mRNA.
DR EMBL; U78165; AAB64246.1; -; mRNA.
DR EMBL; AF084462; AAD13021.1; -; mRNA.
DR EMBL; AF493923; AAM12637.1; -; mRNA.
DR EMBL; AK298768; BAG60910.1; -; mRNA.
DR EMBL; AK314239; BAG36908.1; -; mRNA.
DR EMBL; CR407639; CAG28567.1; -; mRNA.
DR EMBL; AL139128; CAH69943.1; -; Genomic_DNA.
DR EMBL; AL355388; CAH69943.1; JOINED; Genomic_DNA.
DR EMBL; AL355388; CAH72621.1; -; Genomic_DNA.
DR EMBL; AL139128; CAH72621.1; JOINED; Genomic_DNA.
DR EMBL; CH471121; EAW53024.1; -; Genomic_DNA.
DR EMBL; BC104186; AAI04187.1; -; mRNA.
DR EMBL; BC104187; AAI04188.1; -; mRNA.
DR RefSeq; NP_001243749.1; NM_001256820.1.
DR RefSeq; NP_001243750.1; NM_001256821.1.
DR RefSeq; NP_008843.1; NM_006912.5.
DR UniGene; Hs.491234; -.
DR ProteinModelPortal; Q92963; -.
DR SMR; Q92963; 21-217.
DR IntAct; Q92963; 10.
DR STRING; 9606.ENSP00000357306; -.
DR PhosphoSite; Q92963; -.
DR DMDM; 38258628; -.
DR PaxDb; Q92963; -.
DR PRIDE; Q92963; -.
DR Ensembl; ENST00000368322; ENSP00000357305; ENSG00000143622.
DR Ensembl; ENST00000368323; ENSP00000357306; ENSG00000143622.
DR Ensembl; ENST00000539040; ENSP00000441950; ENSG00000143622.
DR GeneID; 6016; -.
DR KEGG; hsa:6016; -.
DR UCSC; uc031pqc.1; human.
DR CTD; 6016; -.
DR GeneCards; GC01M155867; -.
DR HGNC; HGNC:10023; RIT1.
DR HPA; HPA053249; -.
DR MIM; 609591; gene.
DR MIM; 615355; phenotype.
DR neXtProt; NX_Q92963; -.
DR Orphanet; 648; Noonan syndrome.
DR PharmGKB; PA35528; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; Q92963; -.
DR KO; K07832; -.
DR OMA; LKSPFRK; -.
DR OrthoDB; EOG7QVM41; -.
DR PhylomeDB; Q92963; -.
DR Reactome; REACT_111102; Signal Transduction.
DR GeneWiki; RIT1; -.
DR GenomeRNAi; 6016; -.
DR NextBio; 23471; -.
DR PRO; PR:Q92963; -.
DR ArrayExpress; Q92963; -.
DR Bgee; Q92963; -.
DR CleanEx; HS_RIT1; -.
DR Genevestigator; Q92963; -.
DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc.
DR GO; GO:0005516; F:calmodulin binding; TAS:ProtInc.
DR GO; GO:0005525; F:GTP binding; TAS:ProtInc.
DR GO; GO:0003924; F:GTPase activity; IEA:InterPro.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007265; P:Ras protein signal transduction; IDA:UniProtKB.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Complete proteome;
KW Disease mutation; GTP-binding; Membrane; Nucleotide-binding;
KW Reference proteome.
FT CHAIN 1 219 GTP-binding protein Rit1.
FT /FTId=PRO_0000082725.
FT NP_BIND 28 35 GTP (By similarity).
FT NP_BIND 75 79 GTP (By similarity).
FT NP_BIND 134 137 GTP (By similarity).
FT VAR_SEQ 1 36 Missing (in isoform 2).
FT /FTId=VSP_045306.
FT VAR_SEQ 1 1 M -> MERWLFLGATEEGPKRTM (in isoform 3).
FT /FTId=VSP_047114.
FT VARIANT 35 35 S -> T (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070149.
FT VARIANT 57 57 A -> G (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070150.
FT VARIANT 81 81 E -> G (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070151.
FT VARIANT 82 82 F -> L (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070152.
FT VARIANT 82 82 F -> V (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070153.
FT VARIANT 83 83 T -> P (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070154.
FT VARIANT 89 89 Y -> H (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070155.
FT VARIANT 90 90 M -> I (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070156.
FT VARIANT 95 95 G -> A (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070157.
FT MUTAGEN 35 35 S->N: Dominant negative. Loss of
FT interaction with MLLT4, RLF and RALGDS.
FT MUTAGEN 53 53 T->S: Loss of interaction with MLLT4, RLF
FT and RALGDS; when associated with L-79.
FT MUTAGEN 55 55 E->G: Loss of interaction with MLLT4, but
FT not with RLF and RALGDS; when associated
FT with L-79.
FT MUTAGEN 79 79 Q->L: Constitutively active. Dramatic
FT reduction of the rate of GTP hydrolysis.
FT Loss of interaction with MLLT4, RLF and
FT RALGDS; when associated with S-53. Loss
FT of interaction with MLLT4; when
FT associated with G-55.
SQ SEQUENCE 219 AA; 25145 MW; 7F957871F836AE92 CRC64;
MDSGTRPVGS CCSSPAGLSR EYKLVMLGAG GVGKSAMTMQ FISHRFPEDH DPTIEDAYKI
RIRIDDEPAN LDILDTAGQA EFTAMRDQYM RAGEGFIICY SITDRRSFHE VREFKQLIYR
VRRTDDTPVV LVGNKSDLKQ LRQVTKEEGL ALAREFSCPF FETSAAYRYY IDDVFHALVR
EIRRKEKEAV LAMEKKSKPK NSVWKRLKSP FRKKKDSVT
//
ID RIT1_HUMAN Reviewed; 219 AA.
AC Q92963; B4DQE8; O00646; O00720; Q5VY89; Q5VY90;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1997, sequence version 1.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=GTP-binding protein Rit1;
DE AltName: Full=Ras-like protein expressed in many tissues;
DE AltName: Full=Ras-like without CAAX protein 1;
GN Name=RIT1; Synonyms=RIBB, RIT, ROC1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8824319;
RA Lee C.H.J., Della N.G., Chew C.E., Zack D.J.;
RT "Rin, a neuron-specific and calmodulin-binding small G-protein, and
RT Rit define a novel subfamily of ras proteins.";
RL J. Neurosci. 16:6784-6794(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8918462;
RA Wes P.D., Yu M., Montell C.;
RT "RIC, a calmodulin-binding Ras-like GTPase.";
RL EMBO J. 15:5839-5848(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Kawasaki H., Housman D.E., Graybiel A.M.;
RT "Characterization of new small G proteins in the Ras subfamily.";
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION, INTERACTION
RP WITH MLLT4; RALGDS AND RLF, AND MUTAGENESIS OF SER-35; THR-53; GLU-55
RP AND GLN-79.
RC TISSUE=Retina;
RX PubMed=10545207; DOI=10.1006/abbi.1999.1448;
RA Shao H., Kadono-Okuda K., Finlin B.S., Andres D.A.;
RT "Biochemical characterization of the Ras-related GTPases Rit and
RT Rin.";
RL Arch. Biochem. Biophys. 371:207-219(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Esophagus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP FUNCTION, AND INTERACTION WITH BRAF AND RAF1.
RX PubMed=15632082; DOI=10.1128/MCB.25.2.830-846.2005;
RA Shi G.-X., Andres D.A.;
RT "Rit contributes to nerve growth factor-induced neuronal
RT differentiation via activation of B-Raf-extracellular signal-regulated
RT kinase and p38 mitogen-activated protein kinase cascades.";
RL Mol. Cell. Biol. 25:830-846(2005).
RN [12]
RP FUNCTION, VARIANTS NS8 GLY-57; GLY-81; LEU-82 AND ALA-95,
RP CHARACTERIZATION OF VARIANTS NS8 GLY-57; GLY-81; LEU-82 AND ALA-95,
RP AND VARIANTS THR-35; VAL-82; PRO-83 HIS-89 AND ILE-90.
RX PubMed=23791108; DOI=10.1016/j.ajhg.2013.05.021;
RA Aoki Y., Niihori T., Banjo T., Okamoto N., Mizuno S., Kurosawa K.,
RA Ogata T., Takada F., Yano M., Ando T., Hoshika T., Barnett C.,
RA Ohashi H., Kawame H., Hasegawa T., Okutani T., Nagashima T.,
RA Hasegawa S., Funayama R., Nagashima T., Nakayama K., Inoue S.,
RA Watanabe Y., Ogura T., Matsubara Y.;
RT "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK
RT pathway syndrome.";
RL Am. J. Hum. Genet. 93:173-180(2013).
CC -!- FUNCTION: Plays a crucial role in coupling NGF stimulation to the
CC activation of both EPHB2 and MAPK14 signaling pathways and in NGF-
CC dependent neuronal differentiation. Involved in ELK1
CC transactivation through the Ras-MAPK signaling cascade that
CC mediates a wide variety of cellular functions, including cell
CC proliferation, survival, and differentiation.
CC -!- ENZYME REGULATION: Alternates between an inactive form bound to
CC GDP and an active form bound to GTP.
CC -!- SUBUNIT: Interacts with MLLT4, the C-terminal domain of RALGDS and
CC RLF, but not with RIN1 and PIK3CA. RLF binds exclusively to the
CC active GTP-bound form. Strongly interacts with BRAF, but only
CC weakly with RAF1. BARF and RAF1 association is dependent upon the
CC GTP-bound state. Interacts with RGL3 (By similarity).
CC -!- INTERACTION:
CC Q13129:RLF; NbExp=3; IntAct=EBI-365845, EBI-958266;
CC -!- SUBCELLULAR LOCATION: Cell membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q92963-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92963-2; Sequence=VSP_045306;
CC Name=3;
CC IsoId=Q92963-3; Sequence=VSP_047114;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in many tissues.
CC -!- DISEASE: Noonan syndrome 8 (NS8) [MIM:615355]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial
CC dysmorphic features such as hypertelorism, a downward eyeslant and
CC low-set posteriorly rotated ears, and a high incidence of
CC congenital heart defects and hypertrophic cardiomyopathy. Other
CC features can include a short neck with webbing or redundancy of
CC skin, deafness, motor delay, variable intellectual deficits,
CC multiple skeletal defects, cryptorchidism, and bleeding diathesis.
CC Individuals with Noonan syndrome are at risk of juvenile
CC myelomonocytic leukemia, a myeloproliferative disorder
CC characterized by excessive production of myelomonocytic cells.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: Stimulation of the NGF and EGF receptor signaling
CC pathways results in rapid and prolonged activation.
CC -!- MISCELLANEOUS: Shows rapid uncatalyzed guanine nucleotide
CC dissociation rates, which are much faster than those of most Ras
CC subfamily members.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -----------------------------------------------------------------------
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DR EMBL; U71203; AAB42213.1; -; mRNA.
DR EMBL; Y07566; CAA68851.1; -; mRNA.
DR EMBL; U78165; AAB64246.1; -; mRNA.
DR EMBL; AF084462; AAD13021.1; -; mRNA.
DR EMBL; AF493923; AAM12637.1; -; mRNA.
DR EMBL; AK298768; BAG60910.1; -; mRNA.
DR EMBL; AK314239; BAG36908.1; -; mRNA.
DR EMBL; CR407639; CAG28567.1; -; mRNA.
DR EMBL; AL139128; CAH69943.1; -; Genomic_DNA.
DR EMBL; AL355388; CAH69943.1; JOINED; Genomic_DNA.
DR EMBL; AL355388; CAH72621.1; -; Genomic_DNA.
DR EMBL; AL139128; CAH72621.1; JOINED; Genomic_DNA.
DR EMBL; CH471121; EAW53024.1; -; Genomic_DNA.
DR EMBL; BC104186; AAI04187.1; -; mRNA.
DR EMBL; BC104187; AAI04188.1; -; mRNA.
DR RefSeq; NP_001243749.1; NM_001256820.1.
DR RefSeq; NP_001243750.1; NM_001256821.1.
DR RefSeq; NP_008843.1; NM_006912.5.
DR UniGene; Hs.491234; -.
DR ProteinModelPortal; Q92963; -.
DR SMR; Q92963; 21-217.
DR IntAct; Q92963; 10.
DR STRING; 9606.ENSP00000357306; -.
DR PhosphoSite; Q92963; -.
DR DMDM; 38258628; -.
DR PaxDb; Q92963; -.
DR PRIDE; Q92963; -.
DR Ensembl; ENST00000368322; ENSP00000357305; ENSG00000143622.
DR Ensembl; ENST00000368323; ENSP00000357306; ENSG00000143622.
DR Ensembl; ENST00000539040; ENSP00000441950; ENSG00000143622.
DR GeneID; 6016; -.
DR KEGG; hsa:6016; -.
DR UCSC; uc031pqc.1; human.
DR CTD; 6016; -.
DR GeneCards; GC01M155867; -.
DR HGNC; HGNC:10023; RIT1.
DR HPA; HPA053249; -.
DR MIM; 609591; gene.
DR MIM; 615355; phenotype.
DR neXtProt; NX_Q92963; -.
DR Orphanet; 648; Noonan syndrome.
DR PharmGKB; PA35528; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; Q92963; -.
DR KO; K07832; -.
DR OMA; LKSPFRK; -.
DR OrthoDB; EOG7QVM41; -.
DR PhylomeDB; Q92963; -.
DR Reactome; REACT_111102; Signal Transduction.
DR GeneWiki; RIT1; -.
DR GenomeRNAi; 6016; -.
DR NextBio; 23471; -.
DR PRO; PR:Q92963; -.
DR ArrayExpress; Q92963; -.
DR Bgee; Q92963; -.
DR CleanEx; HS_RIT1; -.
DR Genevestigator; Q92963; -.
DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc.
DR GO; GO:0005516; F:calmodulin binding; TAS:ProtInc.
DR GO; GO:0005525; F:GTP binding; TAS:ProtInc.
DR GO; GO:0003924; F:GTPase activity; IEA:InterPro.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007265; P:Ras protein signal transduction; IDA:UniProtKB.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Complete proteome;
KW Disease mutation; GTP-binding; Membrane; Nucleotide-binding;
KW Reference proteome.
FT CHAIN 1 219 GTP-binding protein Rit1.
FT /FTId=PRO_0000082725.
FT NP_BIND 28 35 GTP (By similarity).
FT NP_BIND 75 79 GTP (By similarity).
FT NP_BIND 134 137 GTP (By similarity).
FT VAR_SEQ 1 36 Missing (in isoform 2).
FT /FTId=VSP_045306.
FT VAR_SEQ 1 1 M -> MERWLFLGATEEGPKRTM (in isoform 3).
FT /FTId=VSP_047114.
FT VARIANT 35 35 S -> T (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070149.
FT VARIANT 57 57 A -> G (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070150.
FT VARIANT 81 81 E -> G (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070151.
FT VARIANT 82 82 F -> L (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070152.
FT VARIANT 82 82 F -> V (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070153.
FT VARIANT 83 83 T -> P (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070154.
FT VARIANT 89 89 Y -> H (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070155.
FT VARIANT 90 90 M -> I (probable disease-associated
FT mutation found in patients with features
FT of Noonan syndrome).
FT /FTId=VAR_070156.
FT VARIANT 95 95 G -> A (in NS8; results in increased ELK1
FT transcriptional activation).
FT /FTId=VAR_070157.
FT MUTAGEN 35 35 S->N: Dominant negative. Loss of
FT interaction with MLLT4, RLF and RALGDS.
FT MUTAGEN 53 53 T->S: Loss of interaction with MLLT4, RLF
FT and RALGDS; when associated with L-79.
FT MUTAGEN 55 55 E->G: Loss of interaction with MLLT4, but
FT not with RLF and RALGDS; when associated
FT with L-79.
FT MUTAGEN 79 79 Q->L: Constitutively active. Dramatic
FT reduction of the rate of GTP hydrolysis.
FT Loss of interaction with MLLT4, RLF and
FT RALGDS; when associated with S-53. Loss
FT of interaction with MLLT4; when
FT associated with G-55.
SQ SEQUENCE 219 AA; 25145 MW; 7F957871F836AE92 CRC64;
MDSGTRPVGS CCSSPAGLSR EYKLVMLGAG GVGKSAMTMQ FISHRFPEDH DPTIEDAYKI
RIRIDDEPAN LDILDTAGQA EFTAMRDQYM RAGEGFIICY SITDRRSFHE VREFKQLIYR
VRRTDDTPVV LVGNKSDLKQ LRQVTKEEGL ALAREFSCPF FETSAAYRYY IDDVFHALVR
EIRRKEKEAV LAMEKKSKPK NSVWKRLKSP FRKKKDSVT
//
MIM
609591
*RECORD*
*FIELD* NO
609591
*FIELD* TI
*609591 RIC-LIKE PROTEIN WITHOUT CAAX MOTIF 1; RIT1
;;RAS-LIKE PROTEIN EXPRESSED IN MANY TISSUES; RIT;;
read moreROC1
*FIELD* TX
DESCRIPTION
RIT belongs to the RAS (HRAS; 190020) subfamily of small GTPases (Hynds
et al., 2003).
CLONING
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.
GENE FUNCTION
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.
MAPPING
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.
MOLECULAR GENETICS
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.
*FIELD* AV
.0001
NOONAN SYNDROME 8
RIT1, ALA57GLY
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.
.0002
NOONAN SYNDROME 8
RIT1, GLU81GLY
In a patient with Noonan syndrome-8 (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.
.0003
NOONAN SYNDROME 8
RIT1, PHE82LEU
In 2 unrelated patients with Noonan syndrome-8 (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.
.0004
NOONAN SYNDROME 8
RIT1, GLY95ALA
In 4 unrelated patients with Noonan syndrome-8 (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.
*FIELD* RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Wes, P. D.; Yu, M.; Montell, C.: RIC, a calmodulin-binding Ras-like
GTPase. EMBO J. 15: 5839-5848, 1996.
*FIELD* CN
Cassandra L. Kniffin - updated: 8/1/2013
Ada Hamosh - updated: 2/6/2007
*FIELD* CD
Patricia A. Hartz: 9/20/2005
*FIELD* ED
carol: 08/02/2013
ckniffin: 8/1/2013
alopez: 2/8/2007
terry: 2/6/2007
carol: 9/29/2005
mgross: 9/20/2005
*RECORD*
*FIELD* NO
609591
*FIELD* TI
*609591 RIC-LIKE PROTEIN WITHOUT CAAX MOTIF 1; RIT1
;;RAS-LIKE PROTEIN EXPRESSED IN MANY TISSUES; RIT;;
read moreROC1
*FIELD* TX
DESCRIPTION
RIT belongs to the RAS (HRAS; 190020) subfamily of small GTPases (Hynds
et al., 2003).
CLONING
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.
GENE FUNCTION
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.
MAPPING
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.
MOLECULAR GENETICS
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.
*FIELD* AV
.0001
NOONAN SYNDROME 8
RIT1, ALA57GLY
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.
.0002
NOONAN SYNDROME 8
RIT1, GLU81GLY
In a patient with Noonan syndrome-8 (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.
.0003
NOONAN SYNDROME 8
RIT1, PHE82LEU
In 2 unrelated patients with Noonan syndrome-8 (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.
.0004
NOONAN SYNDROME 8
RIT1, GLY95ALA
In 4 unrelated patients with Noonan syndrome-8 (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.
*FIELD* RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Wes, P. D.; Yu, M.; Montell, C.: RIC, a calmodulin-binding Ras-like
GTPase. EMBO J. 15: 5839-5848, 1996.
*FIELD* CN
Cassandra L. Kniffin - updated: 8/1/2013
Ada Hamosh - updated: 2/6/2007
*FIELD* CD
Patricia A. Hartz: 9/20/2005
*FIELD* ED
carol: 08/02/2013
ckniffin: 8/1/2013
alopez: 2/8/2007
terry: 2/6/2007
carol: 9/29/2005
mgross: 9/20/2005
MIM
615355
*RECORD*
*FIELD* NO
615355
*FIELD* TI
#615355 NOONAN SYNDROME 8; NS8
*FIELD* TX
A number sign (#) is used with this entry because Noonan syndrome-8
read more(NS8) is caused by heterozygous mutation in the RIT1 gene (609591) on
chromosome 1q22.
DESCRIPTION
Noonan syndrome-8 is an autosomal dominant disorder characterized by
short stature, distinctive facial features, and a high incidence of
congenital heart defects and hypertrophic cardiomyopathy. A subset of
patients show intellectual disabilities (summary by Aoki et al., 2013).
For a phenotypic description and a discussion of genetic heterogeneity
of Noonan syndrome, see NS1 (163950).
CLINICAL FEATURES
Aoki et al. (2013) reported 17 unrelated individuals with Noonan
syndrome-8 ranging in age from a few months to 15 years. Patients had a
distinctive facial appearance with relative macrocephaly, hypertelorism,
downslanting palpebral fissures, ptosis, epicanthal folds, and low-set
ears. Many had skin and hair anomalies, such as curly hair, hyperelastic
skin, and hyperkeratosis. Other features included short stature and
short or webbed neck. Twelve individuals (71%) developed hypertrophic
cardiomyopathy, 11 (65%) had pulmonic stenosis, and 5 (29%) had atrial
septal defects. At least 4 patients had documented intellectual
disability. Nine patients showed perinatal abnormalities, including
polyhydramnios, nuchal translucency, and chylothorax. One infant with
cardiomyopathy and pleural effusion died at age 53 days, and 1 child
developed acute lymphoblastic leukemia at age 5 years.
INHERITANCE
The RIT1 mutations identified by Aoki et al. (2013) in 16 patients with
NS8 occurred de novo, consistent with sporadic occurrence of the
disorder. One additional patient inherited a heterozygous mutation from
a mother with a similar phenotype, suggesting rare autosomal dominant
inheritance.
MOLECULAR GENETICS
In 17 (9%) of 180 unrelated patients suspected of having Noonan syndrome
but without mutation in any known Noonan syndrome-causing genes, 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. 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.
*FIELD* RF
1. 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.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Relative macrocephaly;
[Ears];
Low-set ears;
[Eyes];
Hypertelorism;
Epicanthal folds;
Downslanting palpebral fissures;
Ptosis;
[Neck];
Short neck;
Webbed neck
CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Atrial septal defect;
Ventricular septal defect;
Pulmonic stenosis;
Valvular insufficiency
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism
SKIN, NAILS, HAIR:
[Skin];
Hyperelastic skin;
Hyperkeratosis;
[Hair];
Curly hair
NEUROLOGIC:
[Central nervous system];
Intellectual disability (in some patients)
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios;
Fetal pleural effusion
MISCELLANEOUS:
Onset in utero or at birth;
Most mutations occur de novo;
Features are variable
MOLECULAR BASIS:
Caused by mutation in the RIC-like protein without CAAX motif 1 gene
(RIT1, 609591.0001)
*FIELD* CD
Cassandra L. Kniffin: 8/1/2013
*FIELD* ED
joanna: 10/01/2013
ckniffin: 8/1/2013
*FIELD* CD
Cassandra L. Kniffin: 8/1/2013
*FIELD* ED
carol: 08/02/2013
ckniffin: 8/1/2013
*RECORD*
*FIELD* NO
615355
*FIELD* TI
#615355 NOONAN SYNDROME 8; NS8
*FIELD* TX
A number sign (#) is used with this entry because Noonan syndrome-8
read more(NS8) is caused by heterozygous mutation in the RIT1 gene (609591) on
chromosome 1q22.
DESCRIPTION
Noonan syndrome-8 is an autosomal dominant disorder characterized by
short stature, distinctive facial features, and a high incidence of
congenital heart defects and hypertrophic cardiomyopathy. A subset of
patients show intellectual disabilities (summary by Aoki et al., 2013).
For a phenotypic description and a discussion of genetic heterogeneity
of Noonan syndrome, see NS1 (163950).
CLINICAL FEATURES
Aoki et al. (2013) reported 17 unrelated individuals with Noonan
syndrome-8 ranging in age from a few months to 15 years. Patients had a
distinctive facial appearance with relative macrocephaly, hypertelorism,
downslanting palpebral fissures, ptosis, epicanthal folds, and low-set
ears. Many had skin and hair anomalies, such as curly hair, hyperelastic
skin, and hyperkeratosis. Other features included short stature and
short or webbed neck. Twelve individuals (71%) developed hypertrophic
cardiomyopathy, 11 (65%) had pulmonic stenosis, and 5 (29%) had atrial
septal defects. At least 4 patients had documented intellectual
disability. Nine patients showed perinatal abnormalities, including
polyhydramnios, nuchal translucency, and chylothorax. One infant with
cardiomyopathy and pleural effusion died at age 53 days, and 1 child
developed acute lymphoblastic leukemia at age 5 years.
INHERITANCE
The RIT1 mutations identified by Aoki et al. (2013) in 16 patients with
NS8 occurred de novo, consistent with sporadic occurrence of the
disorder. One additional patient inherited a heterozygous mutation from
a mother with a similar phenotype, suggesting rare autosomal dominant
inheritance.
MOLECULAR GENETICS
In 17 (9%) of 180 unrelated patients suspected of having Noonan syndrome
but without mutation in any known Noonan syndrome-causing genes, 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. 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.
*FIELD* RF
1. 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.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Relative macrocephaly;
[Ears];
Low-set ears;
[Eyes];
Hypertelorism;
Epicanthal folds;
Downslanting palpebral fissures;
Ptosis;
[Neck];
Short neck;
Webbed neck
CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Atrial septal defect;
Ventricular septal defect;
Pulmonic stenosis;
Valvular insufficiency
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism
SKIN, NAILS, HAIR:
[Skin];
Hyperelastic skin;
Hyperkeratosis;
[Hair];
Curly hair
NEUROLOGIC:
[Central nervous system];
Intellectual disability (in some patients)
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios;
Fetal pleural effusion
MISCELLANEOUS:
Onset in utero or at birth;
Most mutations occur de novo;
Features are variable
MOLECULAR BASIS:
Caused by mutation in the RIC-like protein without CAAX motif 1 gene
(RIT1, 609591.0001)
*FIELD* CD
Cassandra L. Kniffin: 8/1/2013
*FIELD* ED
joanna: 10/01/2013
ckniffin: 8/1/2013
*FIELD* CD
Cassandra L. Kniffin: 8/1/2013
*FIELD* ED
carol: 08/02/2013
ckniffin: 8/1/2013