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NF1 (neurofibromin 1)

Identity

HGNC (Hugo) NF1
Location 17q11.2
Location_base_pair Starts at 26446121 and ends at 26728821 bp from pter ( according to hg18-Mar_2006)  [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.
  

External links

Nomenclature
HGNC (Hugo)NF1   7765
Entrez_Gene (NCBI)NF1  4763  neurofibromin 1
Cards
AtlasNF1ID134
GeneCards (Weizmann)NF1
Ensembl (Hinxton)ENSG00000196712 [Gene_View]  NF1 [Vega]
AceView (NCBI)NF1
Genatlas (Paris)NF1
euGene (Indiana)4763
SOURCE (Stanford)NM_000267 NM_001042492 NM_001128147
Gene Expression (Array Express) ENSG00000196712
Genomic and cartography
GoldenPath (UCSC)NF1  -  17q11.2   chr17:26446121-26728821 +  17q11.2   [Description]    (hg18-Mar_2006)
EnsemblNF1 - 17q11.2 [CytoView]
Mapping of homologs : NCBINF1 [Mapview]
OMIM162200   162210   193520   601321   607785   613113   
Gene and transcription
Gene : Genbank (Entrez)AB209336 AF055023 AF086346 AK024873 AK026658
Reference sequence (RefSeq transcript) :SRSNM_000267 NM_001042492 NM_001128147
Reference transcript : EntrezNM_000267 NM_001042492 NM_001128147
RefSeq genomic : SRSAC_000060 AC_000149 NC_000017 NG_009018 NT_010799 NW_001838430 NW_926772
RefSeq genomic : EntrezAC_000060 AC_000149 NC_000017 NG_009018 NT_010799 NW_001838430 NW_926772
Consensus coding sequences : CCDS NCBINF1
Cluster EST : UnigeneHs.113577 [ SRS ] Hs.113577 [ NCBI ]
Alternative Splicing : Fast-db (Paris)7838
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtP21359 (SRS) P21359 (Expasy) P21359 (Uniprot)
With graphics : InterProP21359
Splice isoforms : VarSplice FASTAP21359(VarSplice FASTA)
Domaine pattern : Prosite (SRS)CRAL_TRIO (PS50191)    RAS_GTPASE_ACTIV_1 (PS00509)    RAS_GTPASE_ACTIV_2 (PS50018)   
Domain pattern : Prosite (Expaxy)CRAL_TRIO (PS50191)    RAS_GTPASE_ACTIV_1 (PS00509)    RAS_GTPASE_ACTIV_2 (PS50018)   
Domains : Interpro (SRS)CRAL_bd_TRIO_C    RasGAP    Rho_GTPase_activation_prot   
Domains : Interpro (EBI)CRAL_bd_TRIO_C    RasGAP    Rho_GTPase_activation_prot   
Related proteins : CluSTrP21359
Domain families : Pfam SRSRasGAP (PF00616)   
Domain families : Pfam SangerRasGAP (PF00616)   
Domain families : Pfam NCBIpfam00616   
Domain families : Smart EMBLRasGAP (SM00323)  SEC14 (SM00516)  
Blocks (Seattle)P21359
Crystal structure of protein : PDB SRS1NF1    2D4Q    2E2X   
Crystal structure of protein : PDBSum1NF1    2D4Q    2E2X   
Crystal structure of protein : IMB1NF1    2D4Q    2E2X   
Crystal structure of protein : PDB RSDB1NF1    2D4Q    2E2X   
HPRD01203
Protein Interaction databases
DIP (DOE-UCLA)P21359
IntAct (EBI)P21359
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBINF1
SNP : GeneSNP UtahNF1
SNP : HGBaseNF1
Genetic variants : HAPMAPNF1
Somatic Mutations in Cancer : COSMICNF1 
Mutations and Diseases : HGMDNF1
Hereditary diseases : OMIM162200    162210    193520    601321    607785    613113   
Hereditary diseases : GENETests162200    162210    193520    601321    607785    613113   
Diseases : Genetic AssociationNF1
General knowledge
Homologs : HomoloGeneNF1
Homology/Alignments : Family Browser UCSCNF1
Phylogenetic Trees/Animal Genes : TreeFamNF1
Chemical/Protein Interactions : CTD4763
Keywords Ontology : AmiGOosteoblast differentiation  metanephros development  response to hypoxia  liver development  negative regulation of endothelial cell proliferation  regulation of cell-matrix adhesion  Ras GTPase activator activity  protein binding  intracellular  nucleus  cytoplasm  signal transduction  Ras protein signal transduction  negative regulation of neuroblast proliferation  brain development  peripheral nervous system development  heart development  visual learning  phosphoinositide 3-kinase cascade  spinal cord development  forebrain astrocyte development  cerebral cortex development  myelination in the peripheral nervous system  actin cytoskeleton organization  collagen fibril organization  adrenal gland development  negative regulation of cell migration  axon  dendrite  positive regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  wound healing  negative regulation of transcription factor import into nucleus  negative regulation of MAP kinase activity  negative regulation of MAPKKK cascade  negative regulation of MAPKKK cascade  pigmentation  positive regulation of neuron apoptosis  regulation of blood vessel endothelial cell migration  regulation of bone resorption  regulation of glial cell differentiation  positive regulation of adenylate cyclase activity  regulation of angiogenesis  sympathetic nervous system development  camera-type eye morphogenesis  negative regulation of oligodendrocyte differentiation  smooth muscle tissue development  artery morphogenesis  forebrain morphogenesis  cognition  regulation of small GTPase mediated signal transduction  
Keywords Ontology : EGO-EBIosteoblast differentiation  metanephros development  response to hypoxia  liver development  negative regulation of endothelial cell proliferation  regulation of cell-matrix adhesion  Ras GTPase activator activity  protein binding  intracellular  nucleus  cytoplasm  signal transduction  Ras protein signal transduction  negative regulation of neuroblast proliferation  brain development  peripheral nervous system development  heart development  visual learning  phosphoinositide 3-kinase cascade  spinal cord development  forebrain astrocyte development  cerebral cortex development  myelination in the peripheral nervous system  actin cytoskeleton organization  collagen fibril organization  adrenal gland development  negative regulation of cell migration  axon  dendrite  positive regulation of Ras GTPase activity  positive regulation of Ras GTPase activity  wound healing  negative regulation of transcription factor import into nucleus  negative regulation of MAP kinase activity  negative regulation of MAPKKK cascade  negative regulation of MAPKKK cascade  pigmentation  positive regulation of neuron apoptosis  regulation of blood vessel endothelial cell migration  regulation of bone resorption  regulation of glial cell differentiation  positive regulation of adenylate cyclase activity  regulation of angiogenesis  sympathetic nervous system development  camera-type eye morphogenesis  negative regulation of oligodendrocyte differentiation  smooth muscle tissue development  artery morphogenesis  forebrain morphogenesis  cognition  regulation of small GTPase mediated signal transduction  
Pathways : BIOCARTAChromatin Remodeling by hSWI/SNF ATP-dependent Complexes [Genes]   
Pathways : KEGGMAPK signaling pathway
Other databases
Probes
Probes : ImagenesNF1 Related clones (RZPD - Berlin)
Literature
PubMed211 Pubmed reference(s) in Entrez
PubGeneNF1

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 :
Huret JL . NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol Haematol. September 1997 .
URL : http://AtlasGeneticsOncology.org/Genes/NF1ID134.html
Wimmer K . NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol Haematol. February 2006 .
URL : http://AtlasGeneticsOncology.org/Genes/NF1ID134.html

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indexed on : Sat Feb 6 13:44:32 CET 2010

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