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NF1 (neurofibromin 1)

Identity

HGNC (Hugo) NF1
LocusID (NCBI) 4763
Location 17q11.2
Location_base_pair Starts at 29421945 and ends at 29704695 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description 60 exons (57 constitutive, 3 alternative); spans 280 kb; presence of 3 cryptic genes: OMGP, EVI2A, and EVI2B ('overlapping genes'), hidden (!) within NF1 intron 27b with an opposite transcription direction.
Transcription at least 4 alternate splicings; ~ 9.0 kb mRNA complete cds; coding sequence: CDS 198..8717

Protein

Description the protein has been called neurofibromin; 2818 and 2839 amino acids (type-1 and type-2 isoform)
Expression is tissue and development stage specific
Function GTPase activating protein (GAP) interacting with p21RAS -> tumour suppressor.
Homology other (GAP); IRA1 and 2, the yeast inhibitors of p21RAS

Mutations

Germinal large submicroscopic deletions in 5-10% of cases, translocations rare and point mutations in app. 85-90% of cases; widely dispersed, with no clustering, unusual splicing mutations yield difficulties in molecular genetic testing, truncating effect in large majority of cases.
Somatic second inactivating mutation occurs in the Schwann cell of benign neurofibromas; additional genetic alterations in this cell lead to malignant transformation; the spectrum of inactivating somatic mutation not fully elucidated, LOH owing to copy number loss and mitotic recombination, point mutations; another inactivating process may involve RNA editing (for the second allele), which gives rise to a truncated neurofibromin having lost it's GAP activity.

Implicated in

Entity neurofibromatosis type 1
Disease autosomal dominant cancer prone disease; neurofibromatosis type 1 (NF1: the same symbol is used for the disease neurofibromatosis type 1 and the gene neurofibromin 1) is an hamartoneoplastic syndrome.
  
Entity Watson syndrome
Disease autosomal dominant disease with cardiac malformations, and, as is found in von Recklinghausen neurofibromatosis, low normal intelligence, café-au-lait spots, and neurofibromas but to a lesser extend.
Oncogenesis in accordance with the two-hit model for neoplasia, as is found in retinoblastoma.
  

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004 rhabID5004

External links

Nomenclature
HGNC (Hugo)NF1   7765
Cards
AtlasNF1ID134
Entrez_Gene (NCBI)NF1  4763  neurofibromin 1
GeneCards (Weizmann)NF1
Ensembl (Hinxton)ENSG00000196712 [Gene_View]  chr17:29421945-29704695 [Contig_View]  NF1 [Vega]
ICGC DataPortalENSG00000196712
AceView (NCBI)NF1
Genatlas (Paris)NF1
WikiGenes4763
SOURCE (Princeton)NM_000267 NM_001042492 NM_001128147
Genomic and cartography
GoldenPath (UCSC)NF1  -  17q11.2   chr17:29421945-29704695 +  17q11.2   [Description]    (hg19-Feb_2009)
EnsemblNF1 - 17q11.2 [CytoView]
Mapping of homologs : NCBINF1 [Mapview]
OMIM162200   162210   193520   601321   607785   613113   
Gene and transcription
Genbank (Entrez)AB209336 AF055023 AF086346 AK024873 AK026658
RefSeq transcript (Entrez)NM_000267 NM_001042492 NM_001128147
RefSeq genomic (Entrez)AC_000149 NC_000017 NC_018928 NG_009018 NT_010783 NW_001838430 NW_004929407
Consensus coding sequences : CCDS (NCBI)NF1
Cluster EST : UnigeneHs.113577 [ NCBI ]
CGAP (NCI)Hs.113577
Alternative Splicing : Fast-db (Paris)GSHG0012380
Alternative Splicing GalleryENSG00000196712
Gene ExpressionNF1 [ NCBI-GEO ]     NF1 [ SEEK ]   NF1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP21359 (Uniprot)
NextProtP21359  [Medical]
With graphics : InterProP21359
Splice isoforms : SwissVarP21359 (Swissvar)
Domaine pattern : Prosite (Expaxy)CRAL_TRIO (PS50191)    RAS_GTPASE_ACTIV_1 (PS00509)    RAS_GTPASE_ACTIV_2 (PS50018)   
Domains : Interpro (EBI)ARM-like    ARM-type_fold    CRAL-TRIO_dom    Neurofibromin    RasGAP    RasGAP_CS    Rho_GTPase_activation_prot   
Related proteins : CluSTrP21359
Domain families : Pfam (Sanger)CRAL_TRIO_2 (PF13716)    RasGAP (PF00616)   
Domain families : Pfam (NCBI)pfam13716    pfam00616   
Domain families : Smart (EMBL)RasGAP (SM00323)  SEC14 (SM00516)  
DMDM Disease mutations4763
Blocks (Seattle)P21359
PDB (SRS)1NF1    2D4Q    2E2X    3P7Z    3PEG    3PG7   
PDB (PDBSum)1NF1    2D4Q    2E2X    3P7Z    3PEG    3PG7   
PDB (IMB)1NF1    2D4Q    2E2X    3P7Z    3PEG    3PG7   
PDB (RSDB)1NF1    2D4Q    2E2X    3P7Z    3PEG    3PG7   
Human Protein AtlasENSG00000196712
Peptide AtlasP21359
HPRD01203
IPIIPI00299512   IPI00304235   IPI00220514   IPI00909675   IPI00910794   IPI00163320   IPI00815649   IPI00220513   IPI00790152   
Protein Interaction databases
DIP (DOE-UCLA)P21359
IntAct (EBI)P21359
FunCoupENSG00000196712
BioGRIDNF1
IntegromeDBNF1
STRING (EMBL)NF1
Ontologies - Pathways
QuickGOP21359
Ontology : AmiGOMAPK cascade  osteoblast differentiation  metanephros development  response to hypoxia  liver development  negative regulation of endothelial cell proliferation  positive regulation of endothelial cell proliferation  regulation of cell-matrix adhesion  negative regulation of cell-matrix adhesion  Ras GTPase activator activity  protein binding  nucleus  nucleolus  cytoplasm  cytoplasm  negative regulation of protein kinase activity  cell communication  Ras protein signal transduction  negative regulation of neuroblast proliferation  brain development  peripheral nervous system development  heart development  skeletal muscle tissue development  phosphatidylethanolamine binding  visual learning  extrinsic apoptotic signaling pathway via death domain receptors  Schwann cell development  phosphatidylinositol 3-kinase signaling  membrane  negative regulation of angiogenesis  spinal cord development  forebrain astrocyte development  neural tube development  cerebral cortex development  myelination in peripheral nervous system  actin cytoskeleton organization  extracellular matrix organization  collagen fibril organization  adrenal gland development  negative regulation of cell migration  axon  dendrite  phosphatidylcholine binding  intrinsic component of the cytoplasmic side of the plasma membrane  regulation of synaptic transmission, GABAergic  regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  negative regulation of Rac protein signal transduction  wound healing  negative regulation of transcription factor import into nucleus  positive regulation of apoptotic process  negative regulation of MAP kinase activity  negative regulation of MAPK cascade  negative regulation of MAPK cascade  pigmentation  positive regulation of neuron apoptotic process  regulation of blood vessel endothelial cell migration  regulation of bone resorption  negative regulation of osteoclast differentiation  regulation of glial cell differentiation  positive regulation of adenylate cyclase activity  regulation of angiogenesis  negative regulation of Ras protein signal transduction  negative regulation of neurotransmitter secretion  negative regulation of fibroblast proliferation  regulation of long-term neuronal synaptic plasticity  sympathetic nervous system development  camera-type eye morphogenesis  negative regulation of astrocyte differentiation  negative regulation of oligodendrocyte differentiation  smooth muscle tissue development  artery morphogenesis  forebrain morphogenesis  cognition  positive regulation of extrinsic apoptotic signaling pathway via death domain receptors  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Ontology : EGO-EBIMAPK cascade  osteoblast differentiation  metanephros development  response to hypoxia  liver development  negative regulation of endothelial cell proliferation  positive regulation of endothelial cell proliferation  regulation of cell-matrix adhesion  negative regulation of cell-matrix adhesion  Ras GTPase activator activity  protein binding  nucleus  nucleolus  cytoplasm  cytoplasm  negative regulation of protein kinase activity  cell communication  Ras protein signal transduction  negative regulation of neuroblast proliferation  brain development  peripheral nervous system development  heart development  skeletal muscle tissue development  phosphatidylethanolamine binding  visual learning  extrinsic apoptotic signaling pathway via death domain receptors  Schwann cell development  phosphatidylinositol 3-kinase signaling  membrane  negative regulation of angiogenesis  spinal cord development  forebrain astrocyte development  neural tube development  cerebral cortex development  myelination in peripheral nervous system  actin cytoskeleton organization  extracellular matrix organization  collagen fibril organization  adrenal gland development  negative regulation of cell migration  axon  dendrite  phosphatidylcholine binding  intrinsic component of the cytoplasmic side of the plasma membrane  regulation of synaptic transmission, GABAergic  regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  negative regulation of Rac protein signal transduction  wound healing  negative regulation of transcription factor import into nucleus  positive regulation of apoptotic process  negative regulation of MAP kinase activity  negative regulation of MAPK cascade  negative regulation of MAPK cascade  pigmentation  positive regulation of neuron apoptotic process  regulation of blood vessel endothelial cell migration  regulation of bone resorption  negative regulation of osteoclast differentiation  regulation of glial cell differentiation  positive regulation of adenylate cyclase activity  regulation of angiogenesis  negative regulation of Ras protein signal transduction  negative regulation of neurotransmitter secretion  negative regulation of fibroblast proliferation  regulation of long-term neuronal synaptic plasticity  sympathetic nervous system development  camera-type eye morphogenesis  negative regulation of astrocyte differentiation  negative regulation of oligodendrocyte differentiation  smooth muscle tissue development  artery morphogenesis  forebrain morphogenesis  cognition  positive regulation of extrinsic apoptotic signaling pathway via death domain receptors  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Pathways : BIOCARTAChromatin Remodeling by hSWI/SNF ATP-dependent Complexes [Genes]   
Pathways : KEGGMAPK signaling pathway    Ras signaling pathway   
Protein Interaction DatabaseNF1
Wikipedia pathwaysNF1
Gene fusion - rearrangments
Rearrangement : COSMICNF1 [17q11.2]  -  ASIC2 [17q11.2]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)NF1
SNP (GeneSNP Utah)NF1
SNP : HGBaseNF1
Genetic variants : HAPMAPNF1
1000_GenomesNF1 
ICGC programENSG00000196712 
Cancer Gene: CensusNF1 
CONAN: Copy Number AnalysisNF1 
Somatic Mutations in Cancer : COSMICNF1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Mendelian genes
DECIPHER (Syndromes)17:29421945-29704695
Mutations and Diseases : HGMDNF1
OMIM162200    162210    193520    601321    607785    613113   
MedgenNF1
GENETestsNF1
Disease Genetic AssociationNF1
Huge Navigator NF1 [HugePedia]  NF1 [HugeCancerGEM]
Genomic VariantsNF1  NF1 [DGVbeta]
Exome VariantNF1
dbVarNF1
ClinVarNF1
snp3D : Map Gene to Disease4763
General knowledge
Homologs : HomoloGeneNF1
Homology/Alignments : Family Browser (UCSC)NF1
Phylogenetic Trees/Animal Genes : TreeFamNF1
Chemical/Protein Interactions : CTD4763
Chemical/Pharm GKB GenePA31572
Drug Sensitivity NF1
Clinical trialNF1
Cancer Resource (Charite)ENSG00000196712
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=NF1
Probes
Litterature
PubMed341 Pubmed reference(s) in Entrez
CoreMineNF1
GoPubMedNF1
iHOPNF1

Bibliography

A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations.
Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P
Cell. 1990 ; 62 (1) : 193-201.
PMID 2114220
 
Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.
Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA
Cell. 1990 ; 62 (1) : 187-192.
PMID 1694727
 
Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients.
Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL
Science (New York, N.Y.). 1990 ; 249 (4965) : 181-186.
PMID 2134734
 
Watson syndrome: is it a subtype of type 1 neurofibromatosis?
Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS
Journal of medical genetics. 1991 ; 28 (11) : 752-756.
PMID 1770531
 
Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.
Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R, Thakker N
American journal of human genetics. 1993 ; 53 (1) : 90-95.
PMID 8317503
 
Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis.
Legius E, Marchuk DA, Collins FS, Glover TW
Nature genetics. 1993 ; 3 (2) : 122-126.
PMID 8499945
 
Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders.
Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, McCormick F
The New England journal of medicine. 1994 ; 330 (9) : 597-601.
PMID 8302341
 
Genomic organization of the neurofibromatosis 1 gene (NF1).
Li Y, O'Connell P, Breidenbach HH, Cawthon R, Stevens J, Xu G, Neil S, Robertson M, White R, Viskochil D
Genomics. 1995 ; 25 (1) : 9-18.
PMID 7774960
 
Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I.
Metheny LJ, Cappione AJ, Skuse GR
Journal of neuropathology and experimental neurology. 1995 ; 54 (6) : 753-760.
PMID 7595647
 
A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors.
Cappione AJ, French BL, Skuse GR
American journal of human genetics. 1997 ; 60 (2) : 305-312.
PMID 9012403
 
Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.
Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD
Human mutation. 2000 ; 15 (6) : 541-555.
PMID 10862084
 
Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene.
Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner VF
Human mutation. 2004 ; 23 (2) : 111-116.
PMID 14722914
 
Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients.
Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglbˆck H, Maertens O, Messiaen L
Genes, chromosomes & cancer. 2006 ; 45 (3) : 265-276.
PMID 16283621
 
Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations.
Serra E, Rosenbaum T, Winner U, Aledo R, Ars E, Estivill X, Lenard HG, Lˆ°zaro C
Human molecular genetics. 2000 ; 9 (20) : 3055-3064.
PMID 11115850
 
Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas.
Serra E, Rosenbaum T, Nadal M, Winner U, Ars E, Estivill X, Lˆ°zaro C
Nature genetics. 2001 ; 28 (3) : 294-296.
PMID 11431704
 
High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene.
Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF
American journal of human genetics. 2004 ; 75 (3) : 410-423.
PMID 15257518
 
NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.
De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B
American journal of human genetics. 2005 ; 77 (6) : 1092-1101.
PMID 16380919
 
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Contributor(s)

Written09-1997Jean-Loup Huret
Updated02-2006Katharina Wimmer

Citation

This paper should be referenced as such :
Wimmer, K
NF1 (neurofibromin 1)
Atlas Genet Cytogenet Oncol Haematol. 2006;10(3):171-172.
Free online version   Free pdf version   [Bibliographic record ]
Atlas Genet Cytogenet Oncol Haematol. September 1997
http://documents.irevues.inist.fr/bitstream/handle/2042/32021/09-1997-NF1ID134.pdf
URL : http://AtlasGeneticsOncology.org/Genes/NF1ID134.html

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indexed on : Sat Nov 8 16:59:04 CET 2014

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