RBCC Red Blood Cell Collection

NRAS (HRAS1) [Confidence: high (present in two of the MS resources)]
GTPase NRas (Transforming protein N-Ras; Flags: Precursor)

hRBCD IPI00000005
IPI00000005 Transforming protein N-Ras Transforming protein N-Ras membrane n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a 1 cytoplasmic and membrane associated n/a found at its expected molecular weight found at molecular weight

UniProt P01111
ID RASN_HUMAN Reviewed; 189 AA.
AC P01111; Q14971; Q15104; Q15282;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=GTPase NRas;
DE AltName: Full=Transforming protein N-Ras;
DE Flags: Precursor;
GN Name=NRAS; Synonyms=HRAS1;
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 [GENOMIC DNA].
RX PubMed=6616621; DOI=10.1016/0092-8674(83)90390-2;
RA Taparowsky E., Shimizu K., Goldfarb M., Wigler M.;
RT "Structure and activation of the human N-ras gene.";
RL Cell 34:581-586(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2991860; DOI=10.1093/nar/13.14.5255;
RA Hall A., Brown R.;
RT "Human N-ras: cDNA cloning and gene structure.";
RL Nucleic Acids Res. 13:5255-5268(1985).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Fibrosarcoma;
RX PubMed=6086315;
RA Brown R., Marshall C.J., Pennie S.G., Hall A.;
RT "Mechanism of activation of an N-ras gene in the human fibrosarcoma
RT cell line HT1080.";
RL EMBO J. 3:1321-1326(1984).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Lung carcinoma;
RX PubMed=6587382; DOI=10.1073/pnas.81.12.3670;
RA Yuasa Y., Gol R.A., Chang A., Chiu I.-M., Reddy E.P., Tronick S.R.,
RA Aaronson S.A.;
RT "Mechanism of activation of an N-ras oncogene of SW-1271 human lung
RT carcinoma cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:3670-3674(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 [8]
RP NUCLEOTIDE SEQUENCE OF 1-96, AND VARIANT CYS-12.
RC TISSUE=Leukemia;
RX PubMed=2998510;
RA Hirai H., Tanaka S., Azuma M., Anraku Y., Kobayashi Y., Fujisawa M.,
RA Okabe T., Urabe A., Takaku F.;
RT "Transforming genes in human leukemia cells.";
RL Blood 66:1371-1378(1985).
RN [9]
RP NUCLEOTIDE SEQUENCE OF 1-29 AND 43-78.
RX PubMed=1970154;
RA Yuasa Y., Kamiyama T., Kato M., Iwama T., Ikeuchi T., Tonomura A.;
RT "Transforming genes from familial adenomatous polyposis patient cells
RT detected by a tumorigenicity assay.";
RL Oncogene 5:589-596(1990).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 38-96.
RX PubMed=3856237; DOI=10.1073/pnas.82.3.879;
RA Gambke C., Hall A., Moroni C.;
RT "Activation of an N-ras gene in acute myeloblastic leukemia through
RT somatic mutation in the first exon.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:879-882(1985).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 38-96.
RC TISSUE=Bone marrow;
RX PubMed=3295562; DOI=10.1038/327430a0;
RA Hirai H., Kobayashi Y., Mano H., Hagiwara K., Maru Y., Omine M.,
RA Mizoguchi H., Nishida J., Takaku F.;
RT "A point mutation at codon 13 of the N-ras oncogene in myelodysplastic
RT syndrome.";
RL Nature 327:430-432(1987).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 60-96, AND VARIANT ARG-61.
RX PubMed=3276402;
RA Raybaud F., Noguchi T., Marics I., Adelaide J., Planche J., Batoz M.,
RA Aubet C., de Lapeyriere O., Birnbaum D.;
RT "Detection of a low frequency of activated ras genes in human
RT melanomas using a tumorigenicity assay.";
RL Cancer Res. 48:950-953(1988).
RN [13]
RP PALMITOYLATION AT CYS-181, AND ISOPRENYLATION AT CYS-186.
RX PubMed=2661017; DOI=10.1016/0092-8674(89)90054-8;
RA Hancock J.F., Magee A.I., Childs J.E., Marshall C.J.;
RT "All ras proteins are polyisoprenylated but only some are
RT palmitoylated.";
RL Cell 57:1167-1177(1989).
RN [14]
RP PALMITOYLATION AT CYS-181.
RX PubMed=16000296; DOI=10.1074/jbc.M504113200;
RA Swarthout J.T., Lobo S., Farh L., Croke M.R., Greentree W.K.,
RA Deschenes R.J., Linder M.E.;
RT "DHHC9 and GCP16 constitute a human protein fatty acyltransferase with
RT specificity for H- and N-Ras.";
RL J. Biol. Chem. 280:31141-31148(2005).
RN [15]
RP PALMITOYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=15705808; DOI=10.1126/science.1105654;
RA Rocks O., Peyker A., Kahms M., Verveer P.J., Koerner C.,
RA Lumbierres M., Kuhlmann J., Waldmann H., Wittinghofer A.,
RA Bastiaens P.I.H.;
RT "An acylation cycle regulates localization and activity of
RT palmitoylated Ras isoforms.";
RL Science 307:1746-1752(2005).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP INTERACTION WITH RASSF7.
RX PubMed=21278800; DOI=10.1038/cdd.2010.137;
RA Takahashi S., Ebihara A., Kajiho H., Kontani K., Nishina H.,
RA Katada T.;
RT "RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting
RT the activity of phosphorylated-MKK7.";
RL Cell Death Differ. 18:645-655(2011).
RN [18]
RP VARIANT COLORECTAL CANCER ARG-13.
RX PubMed=3102434;
RA Nitta N., Ochiai M., Nagao M., Sugimura T.;
RT "Amino-acid substitution at codon 13 of the N-ras oncogene in rectal
RT cancer in a Japanese patient.";
RL Jpn. J. Cancer Res. 78:21-26(1987).
RN [19]
RP VARIANT ALPS4 ASP-13.
RX PubMed=17517660; DOI=10.1073/pnas.0702975104;
RA Oliveira J.B., Bidere N., Niemela J.E., Zheng L., Sakai K., Nix C.P.,
RA Danner R.L., Barb J., Munson P.J., Puck J.M., Dale J., Straus S.E.,
RA Fleisher T.A., Lenardo M.J.;
RT "NRAS mutation causes a human autoimmune lymphoproliferative
RT syndrome.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:8953-8958(2007).
RN [20]
RP VARIANTS NS6 ILE-50 AND GLU-60, AND CHARACTERIZATION OF VARIANTS NS6
RP ILE-50 AND GLU-60.
RX PubMed=19966803; DOI=10.1038/ng.497;
RA Cirstea I.C., Kutsche K., Dvorsky R., Gremer L., Carta C., Horn D.,
RA Roberts A.E., Lepri F., Merbitz-Zahradnik T., Konig R., Kratz C.P.,
RA Pantaleoni F., Dentici M.L., Joshi V.A., Kucherlapati R.S.,
RA Mazzanti L., Mundlos S., Patton M.A., Silengo M.C., Rossi C.,
RA Zampino G., Digilio C., Stuppia L., Seemanova E., Pennacchio L.A.,
RA Gelb B.D., Dallapiccola B., Wittinghofer A., Ahmadian M.R.,
RA Tartaglia M., Zenker M.;
RT "A restricted spectrum of NRAS mutations causes Noonan syndrome.";
RL Nat. Genet. 42:27-29(2010).
CC -!- FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase
CC activity.
CC -!- ENZYME REGULATION: Alternates between an inactive form bound to
CC GDP and an active form bound to GTP. Activated by a guanine
CC nucleotide-exchange factor (GEF) and inactivated by a GTPase-
CC activating protein (GAP).
CC -!- SUBUNIT: Interacts (active GTP-bound form preferentially) with
CC RGS14 (By similarity). Interacts (active GTP-bound form) with
CC RASSF7.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side. Golgi apparatus membrane; Lipid-anchor. Note=Shuttles
CC between the plasma membrane and the Golgi apparatus.
CC -!- PTM: Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous
CC cycle of de- and re-palmitoylation regulates rapid exchange
CC between plasma membrane and Golgi.
CC -!- PTM: Acetylation at Lys-104 prevents interaction with guanine
CC nucleotide exchange factors (GEFs) (By similarity).
CC -!- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An
CC aggressive pediatric myelodysplastic syndrome/myeloproliferative
CC disorder characterized by malignant transformation in the
CC hematopoietic stem cell compartment with proliferation of
CC differentiated progeny. Patients have splenomegaly, enlarged lymph
CC nodes, rashes, and hemorrhages. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Noonan syndrome 6 (NS6) [MIM:613224]: 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 -!- DISEASE: Autoimmune lymphoproliferative syndrome 4 (ALPS4)
CC [MIM:614470]: A disorder of apoptosis, characterized by chronic
CC accumulation of non-malignant lymphocytes, defective lymphocyte
CC apoptosis, and an increased risk for the development of
CC hematologic malignancies. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Mutations which change AA 12, 13 or 61 activate the
CC potential of Ras to transform cultured cells and are implicated in
CC a variety of human tumors.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/NRASID92.html";
CC -!- WEB RESOURCE: Name=NRASbase; Note=NRAS mutation db;
CC URL="http://bioinf.uta.fi/NRASbase/";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/nras/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=RAS proteins entry;
CC URL="http://en.wikipedia.org/wiki/RAS_proteins";
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DR EMBL; X02751; CAA26529.1; -; mRNA.
DR EMBL; X00642; CAA25269.1; -; Genomic_DNA.
DR EMBL; X00643; CAA25270.1; -; Genomic_DNA.
DR EMBL; X00644; CAA25271.1; -; Genomic_DNA.
DR EMBL; X00645; CAA25272.1; -; Genomic_DNA.
DR EMBL; L00043; AAA60255.1; -; Genomic_DNA.
DR EMBL; L00040; AAA60255.1; JOINED; Genomic_DNA.
DR EMBL; L00041; AAA60255.1; JOINED; Genomic_DNA.
DR EMBL; L00042; AAA60255.1; JOINED; Genomic_DNA.
DR EMBL; AF493919; AAM12633.1; -; mRNA.
DR EMBL; AY428630; AAQ94397.1; -; Genomic_DNA.
DR EMBL; BC005219; AAH05219.1; -; mRNA.
DR EMBL; M25898; AAA36548.1; -; Genomic_DNA.
DR EMBL; X53291; CAA37384.1; -; Genomic_DNA.
DR EMBL; X53292; CAA37384.1; JOINED; Genomic_DNA.
DR EMBL; K03211; AAA36556.1; -; Genomic_DNA.
DR EMBL; M10055; AAA36556.1; JOINED; Genomic_DNA.
DR EMBL; X05565; CAA29079.1; -; Genomic_DNA.
DR EMBL; X07440; CAA30320.1; -; Genomic_DNA.
DR PIR; A90839; TVHURA.
DR PIR; I38149; I38149.
DR RefSeq; NP_002515.1; NM_002524.4.
DR UniGene; Hs.486502; -.
DR PDB; 3CON; X-ray; 1.65 A; A=1-172.
DR PDBsum; 3CON; -.
DR ProteinModelPortal; P01111; -.
DR SMR; P01111; 1-167.
DR DIP; DIP-1058N; -.
DR IntAct; P01111; 7.
DR MINT; MINT-131535; -.
DR STRING; 9606.ENSP00000358548; -.
DR ChEMBL; CHEMBL2079845; -.
DR PhosphoSite; P01111; -.
DR DMDM; 131883; -.
DR OGP; P01111; -.
DR PaxDb; P01111; -.
DR PeptideAtlas; P01111; -.
DR PRIDE; P01111; -.
DR DNASU; 4893; -.
DR Ensembl; ENST00000369535; ENSP00000358548; ENSG00000213281.
DR GeneID; 4893; -.
DR KEGG; hsa:4893; -.
DR UCSC; uc009wgu.3; human.
DR CTD; 4893; -.
DR GeneCards; GC01M115247; -.
DR HGNC; HGNC:7989; NRAS.
DR HPA; CAB010157; -.
DR MIM; 164790; gene.
DR MIM; 607785; phenotype.
DR MIM; 613224; phenotype.
DR MIM; 614470; phenotype.
DR neXtProt; NX_P01111; -.
DR Orphanet; 3261; Autoimmune lymphoproliferative syndrome.
DR Orphanet; 86834; Juvenile myelomonocytic leukemia.
DR Orphanet; 648; Noonan syndrome.
DR PharmGKB; PA31768; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P01111; -.
DR KO; K07828; -.
DR OMA; RILNEEC; -.
DR OrthoDB; EOG7QVM41; -.
DR PhylomeDB; P01111; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P01111; -.
DR ChiTaRS; NRAS; human.
DR EvolutionaryTrace; P01111; -.
DR GeneWiki; Neuroblastoma_RAS_viral_oncogene_homolog; -.
DR GenomeRNAi; 4893; -.
DR NextBio; 18835; -.
DR PRO; PR:P01111; -.
DR ArrayExpress; P01111; -.
DR Bgee; P01111; -.
DR CleanEx; HS_NRAS; -.
DR Genevestigator; P01111; -.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IEA:Ensembl.
DR GO; GO:0030036; P:actin cytoskeleton organization; IEA:Ensembl.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0035022; P:positive regulation of Rac protein signal transduction; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0032228; P:regulation of synaptic transmission, GABAergic; IEA:Ensembl.
DR GO; GO:0051146; P:striated muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
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 3D-structure; Acetylation; Cell membrane; Complete proteome;
KW Disease mutation; Golgi apparatus; GTP-binding; Lipoprotein; Membrane;
KW Methylation; Nucleotide-binding; Palmitate; Prenylation;
KW Proto-oncogene; Reference proteome.
FT CHAIN 1 186 GTPase NRas.
FT /FTId=PRO_0000043006.
FT PROPEP 187 189 Removed in mature form (By similarity).
FT /FTId=PRO_0000043007.
FT NP_BIND 10 17 GTP.
FT NP_BIND 57 61 GTP.
FT NP_BIND 116 119 GTP.
FT REGION 166 185 Hypervariable region.
FT MOTIF 32 40 Effector region.
FT MOD_RES 186 186 Cysteine methyl ester (By similarity).
FT LIPID 181 181 S-palmitoyl cysteine.
FT LIPID 186 186 S-farnesyl cysteine.
FT VARIANT 12 12 G -> C (in leukemia).
FT /FTId=VAR_021194.
FT VARIANT 13 13 G -> D (in ALPS4).
FT /FTId=VAR_063084.
FT VARIANT 13 13 G -> R (in colorectal cancer).
FT /FTId=VAR_006845.
FT VARIANT 50 50 T -> I (in NS6; hypermorphic mutation).
FT /FTId=VAR_063085.
FT VARIANT 60 60 G -> E (in NS6; hypermorphic mutation).
FT /FTId=VAR_063086.
FT VARIANT 61 61 Q -> K (in neuroblastoma cell).
FT /FTId=VAR_006846.
FT VARIANT 61 61 Q -> R (in lung carcinoma cell and
FT melanoma; dbSNP:rs11554290).
FT /FTId=VAR_006847.
FT MUTAGEN 164 164 R->A: Loss of GTP-binding activity.
FT STRAND 2 9
FT HELIX 16 25
FT STRAND 38 46
FT STRAND 49 57
FT STRAND 76 83
FT HELIX 87 104
FT STRAND 111 116
FT HELIX 127 137
FT STRAND 141 143
FT TURN 146 148
FT HELIX 152 166
SQ SEQUENCE 189 AA; 21229 MW; 6898D3F6815B1EC7 CRC64;
MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG
QEEYSAMRDQ YMRTGEGFLC VFAINNSKSF ADINLYREQI KRVKDSDDVP MVLVGNKCDL
PTRTVDTKQA HELAKSYGIP FIETSAKTRQ GVEDAFYTLV REIRQYRMKK LNSSDDGTQG
CMGLPCVVM
//

MIM 164790
*RECORD*
*FIELD* NO
164790
*FIELD* TI
*164790 NEUROBLASTOMA RAS VIRAL ONCOGENE HOMOLOG; NRAS
;;ONCOGENE NRAS; NRAS1
*FIELD* TX
read more
CLONING

Marshall et al. (1982) identified a gene with transforming activity in 2
different human sarcoma cell lines, a fibrosarcoma (HT1080) and an
embryonal rhabdomyosarcoma (RD). Hall et al. (1983) identified this gene
as a member of the RAS gene family and designated it N-RAS 'after
consultation with Wigler and with Weinberg.' They found that NRAS was
also activated in a promyelocytic leukemia cell line (HL60) and a
neuroblastoma cell line (SK-H-SH). NRAS was present at the same levels
in normal fibroblasts and tumor cells. Hall and Brown (1985) identified
2 main NRAS transcripts of 4.3 kb and 2 kb.

GENE STRUCTURE

Hall and Brown (1985) determined that the NRAS gene contains 7 exons.

MAPPING

By restriction mapping and Southern blot analysis, Hall et al. (1983)
mapped the NRAS gene to chromosome 1. By in situ hybridization, Davis et
al. (1983) assigned the NRAS gene to the short arm of chromosome 1. A
concentration of grains was observed just above the centromere in band
1p13. They commented on the wide dispersion of the oncogenes in the RAS
family; each of the 5 mapped to date was on a separate chromosome. Ryan
et al. (1983) confirmed assignment of HRAS (190020) to chromosome 11,
KRAS2 (190070) to chromosome 12, and NRAS to chromosome 1. Addendum in
proof indicated that the same laboratory had assigned NRAS1 to 1p21-cen.
De Martinville et al. (1984) assigned NRAS to 1p31-cen. By somatic cell
hybrid studies and by in situ hybridization, Rabin et al. (1984)
assigned the NRAS gene to 1p13-p11. By in situ hybridization, Popescu et
al. (1985) also assigned the NRAS locus to 1p13-p11. Povey et al. (1985)
reviewed the conflicting evidence on the site of NRAS on 1p. They found
evidence favoring both 1p22 and 1p12-p11. Dracopoli and Meisler (1990)
concluded from linkage analysis and pulsed field gel electrophoresis
that TSHB (188540), NGFB (162030), and NRAS form a tightly linked gene
cluster located in the same chromosomal band. Their location proximal to
the AMY2B gene in 1p21 and close linkage to the alpha-satellite
centromeric repeat D1Z5 provided strong evidence that the correct
assignment for these 3 loci is 1p13 and not 1p22. Mitchell et al. (1995)
localized NRAS to 1p13.2 and CD2 (186990) and NGFB to 1p13.1. They
concluded that the order is as follows: cen--CD2--NGFB--NRAS--tel.

Using teratomas (see 166950) as a means of 'centromere mapping,' Deka et
al. (1989) estimated the NRAS-centromere distance (y) to be 0.30.

GENE FUNCTION

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.

Haigis et al. (2008) used genetically engineered mice to determine
whether and how the related oncogenes Kras (190070) and Nras regulate
homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in
the colonic epithelium stimulated hyperproliferation in a Mek (see
176872)-dependent manner. Nras(G12D) did not alter the growth properties
of the epithelium, but was able to confer resistance to apoptosis. In
the context of an Apc (611731)-mutant colonic tumor, activation of Kras
led to defects in terminal differentiation and expansion of putative
stem cells within the tumor epithelium. This Kras tumor phenotype was
associated with attenuated signaling through the MAPK pathway (see
176872), and human colon cancer cells expressing mutant Kras were
hypersensitive to inhibition of Raf (see 164760) but not Mek. Haigis et
al. (2008) concluded that their studies demonstrated clear phenotypic
differences between mutant Kras and Nras, and suggested that the
oncogenic phenotype of mutant Kras might be mediated by noncanonical
signaling through Ras effector pathways.

Nazarian et al. (2010) showed that acquired resistance of BRAF(V600E)
(164757.0001)-positive melanomas to PLX4032, a novel class I
RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410)
upregulation or NRAS mutations but not through secondary mutations in
BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines
artificially derived from BRAF(V600E)-positive melanoma cell lines and
validated key findings in PLX4032-resistant tumors and tumor-matched,
short-term cultures from clinical trial patients. Induction of PDGFRB
RNA, protein, and tyrosine phosphorylation emerged as a dominant feature
of acquired PLX4032 resistance in a subset of melanoma sublines,
patient-derived biopsies, and short-term cultures. PDGFRB-upregulated
tumor cells had low activated RAS levels and, when treated with PLX4032,
did not reactivate the MAPK (see 176872) pathway significantly. In
another subset, high levels of activated NRAS resulting from mutations
led to significant MAPK pathway reactivation upon PLX4032 treatment.
Knockdown of PDGFRB or NRAS reduced growth of the respective
PLX4032-resistant subsets. Overexpression of PDGFRB or mutated NRAS
conferred PLX4032 resistance to PLX4032-sensitive parental cell lines.
Importantly, Nazarian et al. (2010) showed that MAPK reactivation
predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010)
concluded that melanomas escape BRAF(V600E) targeting not through
secondary BRAF(V600E) mutations but via receptor tyrosine kinase
(RTK)-mediated activation of alternative survival pathway(s) or
activated RAS-mediated reactivation of the MAPK pathway, suggesting
additional therapeutic strategies.

MOLECULAR GENETICS

- Role in Carcinoma

Using the allele-specific amplification method (ARMS), a highly
sensitive 1-stage allele-specific PCR, Bezieau et al. (2001) evaluated
the incidence of NRAS- and KRAS2-activating mutations (in codons 12, 13,
and 61) in 62 patients with monoclonal gammopathy of undetermined
significance (MGUS), multiple myeloma (MM), or primary plasma cell
leukemia (PPCL), and in human myeloma cell lines (HMCL). Mutations in
one or the other gene, or in both, were found in 54.5% of MM patients at
diagnosis (but in 81% at the time of relapse), 50% of PPCL patients, and
50% of 16 HMCL patients. In contrast, the occurrence of such mutations
was very low in MGUS and indolent MM (12.5%). KRAS2 mutations were
always more frequent than NRAS mutations. Bezieau et al. (2001)
concluded that these early mutations may play a major role in the
oncogenesis of multiple myeloid myeloma and primary plasma cell
leukemia.

Vasko et al. (2003) performed a pooled analysis of 269 mutations in
HRAS, KRAS, and NRAS 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, or 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.

Johnson et al. (2005) found that the 3 human RAS genes, HRAS KRAS, and
NRAS, contain multiple let-7 (see 605386) miRNA 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.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. The Cancer Genome Atlas Research Network (2013) identified
recurrent mutations in the NRAS or KRAS genes in 23/200 (12%) samples.

Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that NRAS was among several genes in their study
whose mutations were often found in subclones, suggesting that they are
often cooperating mutations. The authors also identified other genes
that contained mutations they considered probable initiators.

- Autoimmune Lymphoproliferative Syndrome, Type IV

Oliveira et al. (2007) identified a heterozygous germline mutation in
the NRAS gene (G13D; 164790.0003) in a 49-year-old patient with an
atypical autoimmune lymphoproliferative syndrome, which they designated
type IV (ALPS4; 614470). The patient had a lifelong overexpansion of
lymphocytes, childhood leukemia, and early adulthood lymphoma, both
successfully treated. He had increased serum alpha/beta-positive,
CD4-/CD8- T cells and follicular hyperplasia of the lymph nodes.

- Noonan Syndrome 6

Cirstea et al. (2010) identified 1 of 2 different heterozygous mutations
in the NRAS gene (T50I; 164790.0004 and G60E; 164790.0005) in 5
patients, including a mother and son, with Noonan syndrome-6 (NS6;
613224). The mutations were de novo in 3 patients. In vitro functional
expression studies showed that the mutations resulted in enhanced
stimulus-dependent MAPK activation. The patients were part of a larger
study of 917 affected individuals who were negative for previously known
Noonan-associated gene mutations, suggesting that NRAS mutations are a
rare cause of Noonan syndrome.

ANIMAL MODEL

Mutations in the RB1 gene (614041) predispose humans and mice to tumor
development. Takahashi et al. (2006) assessed the effect of Nras loss on
tumor development in Rb1 heterozygous mice. Loss of 1 or 2 Nras alleles
significantly reduced the severity of pituitary tumors arising in Rb1
+/- animals by enhancing their differentiation. By contrast, C-cell
thyroid adenomas occurring in Rb1 +/- mice progressed to metastatic
medullary carcinomas after loss of Nras. In Rb1/Nras doubly heterozygous
mice, distant medullary thyroid carcinoma metastases were associated
with loss of the remaining wildtype Nras allele. Loss of Nras in
Rb1-deficient C cells resulted in elevated Ras homolog family A (RhoA)
activity, and this was causally linked to the invasiveness and
metastatic behavior of these cells. These findings suggested that the
loss of the protooncogene Nras in certain cellular contexts can promote
malignant tumor progression.

*FIELD* AV
.0001
RECTAL CANCER, SOMATIC
NRAS, GLY13ARG

Nitta et al. (1987) found a G-to-C point mutation at the first letter of
codon 13 in the NRAS gene as the presumed basis for activation of the
gene in a case of rectal cancer (see 114500). The point mutation
resulted in the substitution of arginine for glycine.

.0002
THYROID CARCINOMA, FOLLICULAR, SOMATIC
EPIDERMAL NEVUS, SOMATIC, INCLUDED
NRAS, GLN61ARG

Nikiforova et al. (2003) found that the CAA-CGA mutation of NRAS codon
61, resulting in a gln-to-arg change (Q61R), was present in 70% (12) of
follicular carcinomas (188470) and 55% (6) of follicular adenomas
studied.

Hafner et al. (2012) identified a somatic Q61R mutation in 1 of 72
keratinocytic epidermal nevi (162900).

.0003
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IV
JUVENILE MYELOMONOCYTIC LEUKEMIA, INCLUDED;;
NOONAN SYNDROME 6, INCLUDED
NRAS, GLY13ASP

Oliveira et al. (2007) identified a heterozygous G-to-A transition in
the NRAS gene, resulting in a gly13-to-asp (G13D) substitution, in a
49-year-old patient with autoimmune lymphoproliferative syndrome (ALPS4;
614470). The patient had a lifelong overexpansion of lymphocytes and a
history of childhood leukemia, and early adulthood lymphoma, both
successfully treated. There were no developmental defects. Laboratory
studies showed increased serum alpha/beta, CD4-/CD8- T cells and lymph
node follicular hyperplasia. There was no evidence of CD95
(134637)-mediated apoptosis, but the patient's lymphocytes resisted
death by IL2 (147680) withdrawal, indicating a specific defect in
lymphocyte apoptosis. Further studies of the patient's cells indicated a
decrease of the proapoptotic protein BIM (BCL2L11; 603827), which is
critical for withdrawal-induced mitochondrial apoptosis. In vitro
functional expression studies showed that the G13D mutation resulted in
increased activation of NRAS. Oliveira et al. (2007) noted that the same
mutation had been identified somatically in myeloid and lymphoid
malignancies (Bos et al., 1985; Lubbert et al., 1990).

De Filippi et al. (2009) identified a de novo germline heterozygous G13D
substitution in the NRAS gene in a male infant who presented at age 2
months with juvenile myelomonocytic leukemia (JMML; 607785) and was
later noted to have dysmorphic features suggestive of, but not
diagnostic of, Noonan syndrome (NS6; 613224). Features included short
stature, relative macrocephaly, high forehead, epicanthal folds, long
eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and low
scores on performance tasks. Cardiac studies were normal. There were no
hematologic abnormalities related to ALPS in this patient.

.0004
NOONAN SYNDROME 6
NRAS, THR50ILE

In 2 unrelated boys with Noonan syndrome-6 (613224), Cirstea et al.
(2010) identified a de novo heterozygous 149C-T transition in exon 3 of
the NRAS gene, resulting in a thr50-to-ile (T50I) substitution in a
conserved residue located in the beta-2-beta-3 loop connecting the 2
switch regions. In vitro functional expression studies showed that the
mutant protein resulted in enhanced downstream phosphorylation in the
presence of serum, but did not substantially affect intrinsic GTPase
activity. Molecular modeling indicated that thr50 interacts with the
polar heads of membrane phospholipids and is an integral part of a
region that controls RAS membrane orientation. Cirstea et al. (2010)
hypothesized that the T50I substitution might alter RAS orientation,
increase the interaction of GTP-bound RAS with its effectors, and
enhance a downstream signal flow consistent with a gain of function.

.0005
NOONAN SYNDROME 6
NRAS, GLY60GLU

In 3 patients from 2 unrelated families with Noonan syndrome-6 (613224),
Cirstea et al. (2010) identified a heterozygous 179G-A transition in
exon 3 of the NRAS gene, resulting in a gly60-to-glu (G60E) substitution
in a conserved residue in the switch 2 region. One proband had a de novo
mutation, whereas the other inherited it from his affected mother. In
vitro functional expression studies showed that the mutant protein
resulted in enhanced downstream phosphorylation in the presence of
serum, and that the G60E mutant NRAS protein accumulated constitutively
in the active GTP-bound form, although it appeared to be resistant to
GAP stimulation.

.0006
EPIDERMAL NEVUS, SOMATIC
NRAS, PRO34LEU

Hafner et al. (2012) identified a somatic pro34-to-leu (P34L) mutation
in the NRAS gene in 1 of 72 keratinocytic epidermal nevi (162900).

.0007
EPIDERMAL NEVUS, SOMATIC
NRAS, GLY12ASP

Hafner et al. (2012) identified a somatic gly12-to-asp (G12D) mutation
in the NRAS gene in 1 of 72 keratinocytic epidermal nevi (162900).

Li et al. (2013) showed that a single allele of oncogenic Nras(G12D)
increases hematopoietic stem cell (HSC) proliferation and also increases
reconstituting and self-renewal potential upon serial transplantation in
irradiated mice, all prior to leukemia initiation. Nras(G12D) also
confers long-term self-renewal potential to multipotent progenitors. Li
et al. (2013) found that Nras(G12D) had a bimodal effect on HSCs,
increasing the frequency with which some HSCs divide and reducing the
frequency with which others divide. This mirrored bimodal effects on
reconstituting potential, as rarely dividing Nras(G12D) HSCs outcompeted
wildtype HSCs, whereas frequently dividing Nras(G12D) HSCs did not.
Nras(G12D) caused these effects by promoting STAT5 (601511) signaling,
inducing different transcriptional responses in different subsets of
HSCs. Li et al. (2013) concluded that 1 signal can therefore increase
HSC proliferation, competitiveness, and self-renewal through bimodal
effects on HSC gene expression, cycling, and reconstituting potential.

*FIELD* SA
Davis et al. (1984); Munke et al. (1984); Rabin et al. (1983); Taparowsky
et al. (1983); Yuasa et al. (1984)
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*FIELD* CN
Ada Hamosh - updated: 02/05/2014
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Cassandra L. Kniffin - updated: 1/30/2013
Cassandra L. Kniffin - updated: 8/1/2011
Ada Hamosh - updated: 1/21/2011
Cassandra L. Kniffin - updated: 1/19/2010
Ada Hamosh - updated: 7/29/2008
Carol A. Bocchini - updated: 7/25/2008
Cassandra L. Kniffin - updated: 12/20/2007
Ada Hamosh - updated: 6/29/2007
Patricia A. Hartz - updated: 4/10/2006
Victor A. McKusick - updated: 12/27/2005
Stylianos E. Antonarakis - updated: 3/28/2005
John A. Phillips, III - updated: 9/2/2003
John A. Phillips, III - updated: 8/28/2003
Victor A. McKusick - updated: 9/26/2001

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 02/05/2014
alopez: 11/25/2013
alopez: 7/9/2013
alopez: 2/6/2013
ckniffin: 1/30/2013
terry: 11/29/2012
carol: 2/6/2012
wwang: 8/9/2011
ckniffin: 8/1/2011
carol: 6/17/2011
alopez: 1/24/2011
terry: 1/21/2011
alopez: 1/28/2010
ckniffin: 1/19/2010
carol: 8/15/2008
alopez: 7/31/2008
terry: 7/29/2008
carol: 7/28/2008
carol: 7/25/2008
wwang: 6/5/2008
carol: 5/14/2008
wwang: 1/30/2008
ckniffin: 12/20/2007
alopez: 7/2/2007
terry: 6/29/2007
mgross: 4/14/2006
terry: 4/10/2006
alopez: 1/9/2006
alopez: 12/28/2005
terry: 12/27/2005
mgross: 3/28/2005
alopez: 9/11/2003
alopez: 9/10/2003
alopez: 9/2/2003
alopez: 8/28/2003
carol: 10/4/2001
mcapotos: 10/3/2001
terry: 9/26/2001
carol: 7/30/1998
mark: 10/20/1995
warfield: 4/12/1994
supermim: 3/16/1992
carol: 3/8/1992
carol: 2/1/1992
carol: 1/31/1992

MIM 607785
*RECORD*
*FIELD* NO
607785
*FIELD* TI
#607785 JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
;;LEUKEMIA, JUVENILE MYELOMONOCYTIC
read moreLEUKEMIA, CHRONIC MYELOMONOCYTIC, INCLUDED; CMML, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because juvenile
myelomonocytic leukemia (JMML) can be caused by somatic mutations in
specific genes that result in activation of the RAS signaling pathway,
such as PTPN11 (176876), KRAS (190070), NRAS (164790). Somatic mutation
in the CBL gene (165360) has also been reported.

DESCRIPTION

Juvenile myelomonocytic leukemia is an aggressive pediatric
myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD)
characterized by malignant transformation in the hematopoietic stem cell
compartment with proliferation of differentiated progeny (Loh et al.,
2009). JMML constitutes approximately 30% of childhood cases of
myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999).
Although JMML is a progressive and often rapidly fatal disease without
hematopoietic stem cell transplantation (HSCT), some patients have been
shown to have a prolonged and stable clinical course without HSCT
(Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a
similar disorder with later onset. Both JMML and CMML have a high
frequency of mutations affecting the RAS signaling pathway and show
hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511)
hyperphosphorylation (Loh et al., 2009).

- Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia

In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due
to somatic mutations in the PTPN11, KRAS, and NRAS genes. Additionally,
both germline and somatic mutations in the CBL gene have been found in
patients with JMML, indicating a frequency of 10 to 15% of JMML patients
overall (Loh et al., 2009). Somatic disruptions of the GRAF gene
(ARHGAP26; 605370) have also been found in patients with JMML.

About 10 to 15% of JMML cases arise in children with neurofibromatosis
type I (NF1; 162200) due to germline mutations in the NF1 gene (613113).
In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or
Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations
in the PTPN11, KRAS2, and CBL genes, respectively, also have an
increased risk of developing JMML.

- Genetic Heterogeneity of Chronic Myelomonocytic Leukemia

Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1
(605590) genes have been found in patients with CMML.

CYTOGENETICS

In a patient with chronic myelomonocytic leukemia (CMML) with a
t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the
HIP1 gene (601767) to the platelet-derived growth factor-beta receptor
gene (PDGFRB; 173410). They identified a chimeric transcript containing
the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The
fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the
transmembrane and tyrosine kinase domains of the PDGFRB gene. The
reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein
product was a 180-kD protein when expressed in a murine hematopoietic
cell line and was constitutively tyrosine phosphorylated. Furthermore,
the fusion gene transformed the same mouse hematopoietic cell line to
interleukin-3-independent growth.

In a patient with CMML and an acquired t(5;17)(q33;p13), Magnusson et
al. (2001) demonstrated rabaptin-5 (RABEP1; 603616) as a novel partner
fused in-frame to the 5-prime portion of the PDGFBR gene (173410). The
fusion protein included more than 85% of the native rabaptin-5 fused to
the transmembrane and intracellular tyrosine kinase domains of PDGFRB.
Rabaptin-5 is an essential and rate-limiting component of early
endosomal fusion. The new fusion protein links 2 important pathways of
growth regulation.

MOLECULAR GENETICS

- Mutations Associated with Noonan Syndrome and JMML

Tartaglia et al. (2003) showed that germline mutations in PTPN11 lead to
Noonan syndrome-1 (NS1; 163950) associated with JMML (T73I;
176876.0011), and that somatic mutations in PTPN11 are associated with
isolated JMML. Jongmans et al. (2005) described a patient with Noonan
syndrome and mild JMML who carried a mutation in the PTPN11 gene
(176876.0011).

Schubbert et al. (2006) described a 3-month-old female with Noonan
syndrome-3 (NS3; 609942) and a severe clinical phenotype who presented
with a JMML-like myeloproliferative disorder. The patient was
heterozygous for a mutation in the KRAS gene (T58I; 190070.0011). This
mutation was also present in her buccal cells, but was absent in
parental DNA.

De Filippi et al. (2009) reported a boy who presented in infancy with
JMML and was later noted to have dysmorphic features suggestive of, but
not diagnostic of, Noonan syndrome (see NS6; 613224). Features included
short stature, relative macrocephaly, high forehead, epicanthal folds,
long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and
low scores on performance tasks. Cardiac studies were normal. Genetic
analysis revealed a de novo germline heterozygous mutation in the NRAS
gene (G13D; 164790.0003).

In 3 unrelated patients with a Noonan syndrome-like disorder (613563)
who developed JMML, Perez et al. (2010) identified a heterozygous
germline mutation in the CBL gene (Y371H; 165360.0005). The mutation
occurred de novo in 2 patients and was inherited from an unaffected
father in 1 patient. Leukemia cells of all patients showed somatic loss
of heterozygosity at chromosome 11q23, including the CBL gene. The
findings indicated that germline heterozygous mutations in the CBL gene
are associated with predisposition for the development of JMML.

In 27 of 159 leukemia samples from patients with JMML, Loh et al. (2009)
identified 25 homozygous and 2 heterozygous mutations in the CBL gene.
The mutations were located throughout the linker and RING finger
domains, and Y371H was the most common mutation. Leukemic cells from 3
patients examined in detail had acquired isodisomy of chromosome 11q
including the CBL gene. Each of these 3 patients had a heterozygous
germline CBL mutation, whereas their tumor cells had homozygous
mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high
levels of STAT5 (601511) in response to GM-CSF. These findings indicated
that reduplication of an inherited CBL mutation in a pluripotent
hematopoietic stem cell confers a selective advantage for the homozygous
state. Loh et al. (2009) estimated the frequency of CBL mutations to be
10 to 15% of JMML patients overall. They did not find CBL mutations in
JMML patients with known PTPN11/RAS mutation, indicating that CBL and
PTPN11/RAS mutations are mutually exclusive. The finding that
heterozygous germline mutations may predispose to development of JMML
suggested that CBL acts as a tumor suppressor gene.

- Isolated Juvenile or Chronic Myelomonocytic Leukemia

Jankowska et al. (2009) identified recurrent areas of somatic copy
number-neutral loss of heterozygosity (LOH) and deletions of chromosome
4q24 in patients with MDS/MPD. Subsequent analysis identified somatic
mutations in the TET2 gene (612839) in 6 of 17 cases of chronic
myelomonocytic leukemia.

Abdel-Wahab et al. (2009) identified somatic mutations in the TET2 gene
in 29 (42%) of 69 CMML.

Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified somatic ASXL1 mutations were also found in 19 (43%) of 44
chronic myelomonocytic leukemia samples.

Loh et al. (2009) found isolated CBL mutations in 4 of 44 samples from
patients with CMML, which shares features with JMML.

Muramatsu et al. (2010) identified uniparental disomy of 11q23 in
leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the
CBL gene identified somatic mutations in 5 (10%) of 49 patients.
Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and
KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively.
None of the patients had mutations in the TET2 gene (612839), which had
previously been shown to be present in a significant proportion of
patients with MDS/MPD, including CMML (see Jankowska et al., 2009).
Eighteen (37%) of the 49 patients with JMML studied by Muramatsu et al.
(2010) did not have any of the known pathogenic defects.

Klinakis et al. (2011) identified novel somatic-inactivating Notch (see
190198) pathway mutations in a fraction of patients with CMML.
Inactivation of Notch signaling in mouse hematopoietic stem cells
resulted in aberrant accumulation of granulocyte/monocyte progenitors,
extramedullary hematopoiesis, and the induction of CMML-like disease.
Transcriptome analysis revealed that Notch signaling regulates an
extensive myelomonocytic-specific gene signature, through the direct
suppression of gene transcription by the Notch target Hes1 (139605).
Klinakis et al. (2011) concluded that their studies identified a novel
role for Notch signaling during early hematopoietic stem cell
differentiation and suggested that the Notch pathway can play both
tumor-promoting and -suppressive roles within the same tissue.

Sakaguchi et al. (2013) performed whole-exome sequencing for paired
tumor-normal DNA from 13 individuals with JMML (cases), followed by deep
sequencing of 8 target genes in 92 tumor samples. JMML was characterized
by a paucity of gene mutations (0.85 nonsilent mutations per sample)
with somatic or germline RAS pathway involvement in 82 cases (89%). The
SETBP1 (611060) and JAK3 (600173) mutations were among common targets
for secondary mutations. Mutations in JAK3 were often subclonal, and
Sakaguchi et al. (2013) hypothesized that they may be involved in the
progression rather than the initiation of leukemia; these mutations
associated with poor clinical outcomes.

- Exclusion Studies

Yoshida et al. (2008) excluded mutation in the SIPA1 gene (602180) as a
cause of JMML in 16 specimens obtained from patients with the disorder
who did not have mutations in the KRAS, NRAS, or PTPN11 genes.

GENOTYPE/PHENOTYPE CORRELATIONS

Matsuda et al. (2007) reported 3 with patients with an NRAS or KRAS
gly12-to-ser (G12S) mutation who showed spontaneous improvement of
hematologic abnormalities lasting for 2 to 4 years with neither
intensive therapy nor HSCT. They suggested that the mild course
correlated with the G12S RAS mutation and recommended that patients
found to have this mutation receive close follow-up but no chemotherapy.
Flotho et al. (2008) viewed the recommendation of Matsuda et al. (2007)
as premature. They reviewed 50 patients with JMML who were not given
HSCT within the first 3 years after diagnosis; of these, 17 survived
without treatment from 4 to 21 years. Six of 7 carried a RAS mutation
different from R12S.

*FIELD* RF
1. Abdel-Wahab, O.; Mullally, A.; Hedvat, C.; Garcia-Manero, G.; Patel,
J.; Wadleigh, M.; Malinge, S.; Yao, J.; Kilpivaara, O.; Bhat, R.;
Huberman, K.; Thomas, S.; and 12 others: Genetic characterization
of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:
144-147, 2009.

2. De Filippi, P.; Zecca, M.; Lisini, D.; Rosti, V.; Cagioni, C.;
Carlo-Stella, C.; Radi, O.; Veggiotti, P.; Mastronuzzi, A.; Acquaviva,
A.; D'Ambrosio, A.; Locatelli, F.; Danesino, C.: Germ-line mutation
of the NRAS gene may be responsible for the development of juvenile
myelomonocytic leukaemia. Brit. J. Haematol. 147: 706-709, 2009.

3. Flotho, C.; Kratz, C. P.; Bergstrasser, E.; Hasle, H.; Stary, J.;
Trebo, M.; van den Heuvel-Eibrink, M. M.; Wojcik, D.; Zecca, M.; Locatelli,
F.; Niemeyer, C. M.: Genotype-phenotype correlation in cases of juvenile
myelomonocytic leukemia with clonal RAS mutations. (Letter) Blood 111:
966-967, 2008.

4. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Bonansea, J.; Cervera,
N.; Carbuccia, N.; Lagarde, A.; Prebet, T.; Nezri, M.; Sainty, D.;
Olschwang, S.; Xerri, L.; Chaffanet, M.; Mozziconacci, M.-J.; Vey,
N.; Birnbaum, D.: Mutations of polycomb-associated gene ASXL1 in
myelodysplastic syndromes and chronic myelomonocytic leukaemia. Brit.
J. Haemat. 145: 788-800, 2009.

5. Hasle, H.; Arico, M.; Basso, G.; Biondi, A.; Rajnoldi, A. C.; Creutzig,
U.; Fenu, S.; Fonatsch, C.; Haas, O. A.; Harbott, J.; Kardos, G.;
Kerndrup, G.; and 11 others: Myelodysplastic syndrome, juvenile
myelomonocytic leukemia, and acute myeloid leukemia associated with
complete or partial monosomy 7. Leukemia 13: 376-385, 1999.

6. Jankowska, A. M.; Szpurka, H.; Tiu, R. V.; Makishima, H.; Afable,
M.; Huh, J.; O'Keefe, C. L.; Ganetzky, R.; McDevitt, M. A.; Maciejewski,
J. P.: Loss of heterozygosity 4q24 and TET2 mutations associated
with myelodysplastic/myeloproliferative neoplasms. Blood 113: 6403-6410,
2009.

7. Jongmans, M.; Sistermans, E. A.; Rikken, A.; Nillesen, W. M.; Tamminga,
R.; Patton, M.; Maier, E. M.; Tartaglia, M.; Noordam, K.; van der
Burgt, I.: Genotypic and phenotypic characterization of Noonan syndrome:
new data and review of the literature. Am. J. Med. Genet. 134A:
165-170, 2005.

8. Klinakis, A.; Lobry, C.; Abdel-Wahab, O.; Oh, P.; Haeno, H.; Buonamici,
S.; van De Walle, I.; Cathelin, S.; Trimarchi, T.; Araldi, E.; Liu,
C.; Ibrahim, S.; Beran, M.; Zavadil, J.; Efstratiadis, A.; Taghon,
T.; Michor, F.; Levine, R. L.; Aifantis, I.: A novel tumour-suppressor
function for the Notch pathway in myeloid leukaemia. Nature 473:
230-233, 2011.

9. Loh, M. L.; Sakai, D. S.; Flotho, C.; Kang, M.; Fliegauf, M.; Archambeault,
S.; Mullighan, C. G.; Chen, L.; Bergstraesser, E.; Bueso-Ramos, C.
E.; Emanuel, P. D.; Hasle, H.; and 9 others: Mutations in CBL occur
frequently in juvenile myelomonocytic leukemia. Blood 114: 1859-1863,
2009.

10. Magnusson, M. K.; Meade, K. E.; Brown, K. E.; Arthur, D. C.; Krueger,
L. A.; Barrett, A. J.; Dunbar, C. E.: Rabaptin-5 is a novel fusion
partner to platelet-derived growth factor beta receptor in chronic
myelomonocytic leukemia. Blood 98: 2518-2525, 2001.

11. Matsuda, K.; Shimada, A.; Yoshida, N.; Ogawa, A.; Watanabe, A.;
Yajima, S.; Iizuka, S.; Koike, K.; Yanai, F.; Kawasaki, K.; Yanagimachi,
M.; Kikuchi, A.; and 10 others: Spontaneous improvement of hematologic
abnormalities in patients having juvenile myelomonocytic leukemia
with specific RAS mutations. Blood 109: 5477-5480, 2007.

12. Muramatsu, H.; Makishima, H.; Jankowska, A. M.; Cazzolli, H.;
O'Keefe, C.; Yoshida, N.; Xu, Y.; Nishio, N.; Hama, A.; Yagasaki,
H.; Takahashi, Y.; Kato, K.; Manabe, A.; Kojima, S.; Maciejewski,
J. P.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations
are pathogenic in juvenile myelomonocytic leukemia. Blood 115: 1969-1975,
2010.

13. Niemeyer, C. M.; Arico, M.; Basso, G.; Biondi, A.; Cantu Rajnoldi,
A.; Creutzig, U.; Haas, O.; Harbott, J.; Hasle, H.; Kerndrup, G.;
Locatelli, F.; Mann, G.; Stollmann-Gibbels, B.; van't Veer-Korthof,
E. T.; van Wering, E.; Zimmermann, M.; European Working Group on
Myelodysplastic Syndromes in Childhood (EWOG-MDS): Chronic myelomonocytic
leukemia in childhood: a retrospective analysis of 110 cases. Blood 89:
3534-3543, 1997.

14. Perez, B.; Mechinaud, F.; Galambrun, C.; Ben Romdhane, N.; Isidor,
B.; Philip, N.; Derain-Court, J.; Cassinat, B.; Lachenaud, J.; Kaltenbach,
S.; Salmon, A.; Desiree, C.; Pereira, S.; Menot, M. L.; Royer, N.;
Fenneteau, O.; Baruchel, A.; Chomienne, C.; Verloes, A.; Cave, H.
: Germline mutations of the CBL gene define a new genetic syndrome
with predisposition to juvenile myelomonocytic leukaemia. J. Med.
Genet. 47: 686-691, 2010.

15. Ross, T. S.; Bernard, O. A.; Berger, R.; Gilliland, D. G.: Fusion
of huntingtin interacting protein 1 to platelet-derived growth factor-beta
receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91:
4419-4426, 1998.

16. Sakaguchi, H.; Okuno, Y.; Muramatsu, H.; Yoshida, K.; Shiraishi,
Y.; Takahashi, M.; Kon, A.; Sanada, M.; Chiba, K.; Tanaka, H.; Makishima,
H.; Wang, X.; and 10 others: Exome sequencing identifies secondary
mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nature
Genet. 45: 937-941, 2013.

17. Schubbert, S.; Zenker, M.; Rowe, S. L.; Boll, S.; Klein, C.; Bollag,
G.; van der Burgt, I.; Musante, L.; Kalscheuer, V.; Wehner, L.-E.;
Nguyen, H.; West, B.; Zhang, K. Y. J.; Sistermans, E.; Rauch, A.;
Niemeyer, C. M.; Shannon, K.; Kratz, C. P.: Germline KRAS mutations
cause Noonan syndrome. Nature Genet. 38: 331-336, 2006. Note: Erratum:
Nature Genet. 38: 598 only, 2006.

18. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
syndromes and acute myeloid leukemia. Nature Genet. 34: 148-150,
2003.

19. Yoshida, N.; Yagasaki, H.; Takahashi, Y.; Kudo, K.; Manabe, A.;
Kojima, S.: Mutation analysis of SIPA1 in patients with juvenile
myelomonocytic leukemia. (Letter) Brit. J. Haematol. 142: 845-846,
2008.

*FIELD* CN
Ada Hamosh - updated: 01/28/2014
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 5/25/2011
Ada Hamosh - updated: 5/23/2011
Cassandra L. Kniffin - updated: 5/3/2011
Carol A. Bocchini - updated: 6/1/2009
Cassandra L. Kniffin - updated: 3/9/2009
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 4/14/2005

*FIELD* CD
Victor A. McKusick: 5/14/2003

*FIELD* ED
alopez: 01/28/2014
carol: 12/8/2011
carol: 11/29/2011
ckniffin: 10/24/2011
wwang: 8/9/2011
ckniffin: 8/1/2011
wwang: 6/2/2011
ckniffin: 5/31/2011
ckniffin: 5/25/2011
alopez: 5/24/2011
terry: 5/23/2011
wwang: 5/19/2011
ckniffin: 5/3/2011
carol: 11/23/2009
terry: 6/19/2009
terry: 6/1/2009
carol: 6/1/2009
wwang: 3/18/2009
ckniffin: 3/9/2009
carol: 7/31/2008
alopez: 3/3/2006
terry: 2/24/2006
tkritzer: 4/27/2005
terry: 4/14/2005
terry: 7/30/2003
alopez: 6/3/2003
alopez: 5/15/2003
alopez: 5/14/2003

MIM 613224
*RECORD*
*FIELD* NO
613224
*FIELD* TI
#613224 NOONAN SYNDROME 6; NS6
*FIELD* TX
A number sign (#) is used with this entry because this form of Noonan
read moresyndrome (NS6) is caused by heterozygous mutation in the NRAS gene
(164790) on chromosome 1p13.

For a general phenotypic description and a discussion of genetic
heterogeneity of Noonan syndrome, see NS1 (163950).

CLINICAL FEATURES

Cirstea et al. (2010) reported 4 unrelated probands with Noonan
syndrome-6. One proband had an affected mother. The ages of the patients
ranged from 3.3 to 50 years. All patients had typical and somewhat
variable clinical features of Noonan syndrome, including characteristic
facial features such as hypertelorism and low-set ears, short stature,
webbed neck, curly hair, thorax deformities, hypotonia, and
cryptorchidism in males. One had speech delay, 2 had borderline mental
retardation, and 2 had normal development. Three had congenital heart
defects, including hypertrophic cardiomyopathy and pulmonic stenosis.
Other features included macrocephaly (in 3 patients), myopia (in 2), and
hyperkeratosis (in 4). The patients were part of a larger study of 917
affected individuals who were negative for previously known
Noonan-associated gene mutations.

- Clinical Variability

De Filippi et al. (2009) reported a boy who presented in infancy with
juvenile myelomonocytic leukemia (JMML; 607785) and was later noted to
have dysmorphic features suggestive of, but not diagnostic of, Noonan
syndrome. Features included short stature, relative macrocephaly, high
forehead, epicanthal folds, long eyebrows, low nasal bridge, low-set
ears, 2 cafe-au-lait spots, and low scores on performance tasks. Cardiac
studies were normal. Genetic analysis revealed a de novo germline
heterozygous mutation in the NRAS gene (G13D; 164790.0003).

MOLECULAR GENETICS

In 5 patients, including a mother and son, with Noonan syndrome-6,
Cirstea et al. (2010) identified 1 of 2 different heterozygous mutations
in the NRAS gene (T50I; 164790.0004 and G60E; 164790.0005). The
mutations were de novo in 3 patients. In vitro functional expression
studies showed that both mutations resulted in increased NRAS activity
consistent with a gain of function.

*FIELD* RF
1. Cirstea, I. C.; Kutsche, K.; Dvorsky, R.; Gremer, L.; Carta, C.;
Horn, D.; Roberts, A. E.; Lepri, F.; Merbitz-Zahradnik, T.; Konig,
R.; Kratz, C. P.; Pantaleoni, F.; and 19 others: A restricted spectrum
of NRAS mutations cause Noonan syndrome. Nature. Genet. 42: 27-29,
2010.

2. De Filippi, P.; Zecca, M.; Lisini, D.; Rosti, V.; Cagioni, C.;
Carlo-Stella, C.; Radi, O.; Veggiotti, P.; Mastronuzzi, A.; Acquaviva,
A.; D'Ambrosio, A.; Locatelli, F.; Danesino, C.: Germ-line mutation
of the NRAS gene may be responsible for the development of juvenile
myelomonocytic leukaemia. Brit. J. Haematol. 147: 706-709, 2009.

*FIELD* CN
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 1/19/2010

*FIELD* CD
Cassandra L. Kniffin: 1/15/2010

*FIELD* ED
terry: 03/27/2012
wwang: 8/9/2011
ckniffin: 8/1/2011
alopez: 1/28/2010
ckniffin: 1/19/2010

MIM 614470
*RECORD*
*FIELD* NO
614470
*FIELD* TI
#614470 AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IV; ALPS4
*FIELD* TX
A number sign (#) is used with this entry because of evidence that a
read moreform of autoimmune lymphoproliferative syndrome, designated type IV
(ALPS4), is caused by heterozygous mutation in the NRAS gene (164790) on
chromosome 1p13.

DESCRIPTION

Autoimmune lymphoproliferative syndromes are characterized by chronic
accumulation of nonmalignant lymphocytes, defective lymphocyte
apoptosis, and an increased risk for the development of hematologic
malignancies. ALPS IV is the first form known to be caused by abnormal
intrinsic pathway apoptosis (summary by Oliveira et al., 2007).

For a general phenotypic description and a discussion of genetic
heterogeneity of ALPS, see 601859.

CLINICAL FEATURES

Oliveira et al. (2007) reported a 49-year-old patient with autoimmune
lymphoproliferative syndrome who had a lifelong overexpansion of
lymphocytes and a history of childhood leukemia and early adulthood
lymphoma, both successfully treated. There were no developmental
defects. Laboratory studies showed increased serum alpha/beta, CD4-/CD8-
T cells and lymph node follicular hyperplasia. There was no evidence of
CD95 (134637)-mediated apoptosis, but the patient's lymphocytes resisted
death by IL2 (147680) withdrawal, indicating a specific defect in
lymphocyte apoptosis. Further studies of the patient's cells indicated a
decrease of the proapoptotic protein BIM (BCL2L11; 603827), which is
critical for withdrawal-induced mitochondrial apoptosis.

MOLECULAR GENETICS

In a patient with ALPS type IV, Oliveira et al. (2007) identified a
heterozygous G-to-A transition in the NRAS gene, resulting in a
gly13-to-asp substitution (G13D; 164790.0003). In vitro functional
expression studies showed that the G13D mutation resulted in increased
activation of NRAS.

*FIELD* RF
1. Oliveira, J. B.; Bidere, N.; Niemela, J. E.; Zheng, L.; Sakai,
K.; Nix, C. P.; Danner, R. L.; Barb, J.; Munson, P. J.; Puck, J. M.;
Dale, J.; Straus, S. E.; Fleisher, T. A.; Lenardo, M. J.: NRAS mutation
causes a human autoimmune lymphoproliferative syndrome. Proc. Nat.
Acad. Sci. 104: 8953-8958, 2007.

*FIELD* CD
Carol A. Bocchini: 2/6/2012

*FIELD* ED
carol: 02/06/2012