NF1 (neurofibromin 1)

Identity

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

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	NF1   7765
Entrez_Gene	NF1  4763  neurofibromin 1
	Cards
Atlas	NF1ID134
GeneCards	NF1
Ensembl	NF1 [Search_View]   ENSG00000196712 [Gene_View]
Genatlas	NF1
GeneLynx	NF1
eGenome	NF1
euGene	4763
	Genomic and cartography
GoldenPath	NF1  -  17q11.2   chr17:26446121-26728821 +  17q11.2   [Description]    (hg18-Mar_2006)
Ensembl	NF1 - 17q11.2 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	NF1
	Gene and transcription
Genbank	AB209336 [ ENTREZ ]
Genbank	AF055023 [ ENTREZ ]
Genbank	AF086346 [ ENTREZ ]
Genbank	AK024873 [ ENTREZ ]
Genbank	AK026658 [ ENTREZ ]
RefSeq	NM_000267 [ SRS ]    NM_000267 [ ENTREZ ]
RefSeq	NM_001042492 [ SRS ]    NM_001042492 [ ENTREZ ]
RefSeq	NM_001128147 [ SRS ]    NM_001128147 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	AC_000149 [ SRS ]    AC_000149 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NT_010799 [ SRS ]    NT_010799 [ ENTREZ ]
RefSeq	NW_001838430 [ SRS ]    NW_001838430 [ ENTREZ ]
RefSeq	NW_926772 [ SRS ]    NW_926772 [ ENTREZ ]
AceView	NF1 AceView - NCBI
Unigene	Hs.113577 [ SRS ]    Hs.113577 [ NCBI ]     HS113577 [ spliceNest ]
Fast-db	7838 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P21359 [ SRS]    P21359 [ EXPASY ]     P21359 [ INTERPRO ]     P21359 [ UNIPROT ]
Prosite	PS50191 CRAL_TRIO [ SRS ]    PS50191 CRAL_TRIO [ Expasy ]
Prosite	PS00509 RAS_GTPASE_ACTIV_1 [ SRS ]    PS00509 RAS_GTPASE_ACTIV_1 [ Expasy ]
Prosite	PS50018 RAS_GTPASE_ACTIV_2 [ SRS ]    PS50018 RAS_GTPASE_ACTIV_2 [ Expasy ]
Interpro	IPR001251 CRAL_bd_TRIO_C [ SRS ]    IPR001251 CRAL_bd_TRIO_C [ EBI ]
Interpro	IPR001936 RasGAP [ SRS ]    IPR001936 RasGAP [ EBI ]
CluSTr	P21359
Pfam	PF00616 RasGAP [ SRS ]    PF00616 RasGAP [ Sanger ]    pfam00616 [ NCBI-CDD ]
Smart	SM00323 RasGAP [EMBL]
Smart	SM00516 SEC14 [EMBL]
Blocks	P21359
PDB	1NF1 [ SRS ]    1NF1 [ PdbSum ],   1NF1 [ IMB ]   1NF1 [ RSDB ]
PDB	2D4Q [ SRS ]    2D4Q [ PdbSum ],   2D4Q [ IMB ]   2D4Q [ RSDB ]
PDB	2E2X [ SRS ]    2E2X [ PdbSum ],   2E2X [ IMB ]   2E2X [ RSDB ]
HPRD	01203
	Protein Interaction databases
DIP	P21359
IntAct	P21359
	Polymorphism : SNP, mutations, diseases
OMIM	162200;162210;193520;601321;607785    [ map ]
GENECLINICS	162200;162210;193520;601321;607785
SNP	NF1 [dbSNP-NCBI]
SNP	NM_000267 [SNP-NCI]
SNP	NM_001042492 [SNP-NCI]
SNP	NM_001128147 [SNP-NCI]
SNP	NF1 [GeneSNPs - Utah]  NF1] [HGBASE - SRS]
HAPMAP	NF1 [HAPMAP]
COSMIC	NF1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	NF1
	General knowledge
Family Browser	NF1 [UCSC Family Browser]
SOURCE	NM_000267
SOURCE	NM_001042492
SOURCE	NM_001128147
SMD	Hs.113577
SAGE	Hs.113577
GO	osteoblast differentiation [Amigo]  osteoblast differentiation
GO	metanephros development [Amigo]  metanephros development
GO	response to hypoxia [Amigo]  response to hypoxia
GO	liver development [Amigo]  liver development
GO	negative regulation of endothelial cell proliferation [Amigo]  negative regulation of endothelial cell proliferation
GO	regulation of cell-matrix adhesion [Amigo]  regulation of cell-matrix adhesion
GO	molecular_function [Amigo]  molecular_function
GO	GTPase activator activity [Amigo]  GTPase activator activity
GO	Ras GTPase activator activity [Amigo]  Ras GTPase activator activity
GO	protein binding [Amigo]  protein binding
GO	cellular_component [Amigo]  cellular_component
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	cytoplasm [Amigo]  cytoplasm
GO	signal transduction [Amigo]  signal transduction
GO	Ras protein signal transduction [Amigo]  Ras protein signal transduction
GO	negative regulation of neuroblast proliferation [Amigo]  negative regulation of neuroblast proliferation
GO	brain development [Amigo]  brain development
GO	peripheral nervous system development [Amigo]  peripheral nervous system development
GO	heart development [Amigo]  heart development
GO	biological_process [Amigo]  biological_process
GO	visual learning [Amigo]  visual learning
GO	phosphoinositide 3-kinase cascade [Amigo]  phosphoinositide 3-kinase cascade
GO	spinal cord development [Amigo]  spinal cord development
GO	forebrain astrocyte development [Amigo]  forebrain astrocyte development
GO	cerebral cortex development [Amigo]  cerebral cortex development
GO	myelination in the peripheral nervous system [Amigo]  myelination in the peripheral nervous system
GO	actin cytoskeleton organization and biogenesis [Amigo]  actin cytoskeleton organization and biogenesis
GO	collagen fibril organization [Amigo]  collagen fibril organization
GO	adrenal gland development [Amigo]  adrenal gland development
GO	negative regulation of cell migration [Amigo]  negative regulation of cell migration
GO	axon [Amigo]  axon
GO	dendrite [Amigo]  dendrite
GO	positive regulation of Ras GTPase activity [Amigo]  positive regulation of Ras GTPase activity
GO	wound healing [Amigo]  wound healing
GO	negative regulation of transcription factor import into nucleus [Amigo]  negative regulation of transcription factor import into nucleus
GO	negative regulation of MAP kinase activity [Amigo]  negative regulation of MAP kinase activity
GO	negative regulation of MAPKKK cascade [Amigo]  negative regulation of MAPKKK cascade
GO	pigmentation [Amigo]  pigmentation
GO	positive regulation of neuron apoptosis [Amigo]  positive regulation of neuron apoptosis
GO	regulation of blood vessel endothelial cell migration [Amigo]  regulation of blood vessel endothelial cell migration
GO	regulation of bone resorption [Amigo]  regulation of bone resorption
GO	regulation of glial cell differentiation [Amigo]  regulation of glial cell differentiation
GO	positive regulation of adenylate cyclase activity [Amigo]  positive regulation of adenylate cyclase activity
GO	regulation of angiogenesis [Amigo]  regulation of angiogenesis
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
GO	sympathetic nervous system development [Amigo]  sympathetic nervous system development
GO	camera-type eye morphogenesis [Amigo]  camera-type eye morphogenesis
GO	negative regulation of oligodendrocyte differentiation [Amigo]  negative regulation of oligodendrocyte differentiation
GO	smooth muscle development [Amigo]  smooth muscle development
GO	artery morphogenesis [Amigo]  artery morphogenesis
GO	forebrain morphogenesis [Amigo]  forebrain morphogenesis
GO	cognition [Amigo]  cognition
GO	regulation of small GTPase mediated signal transduction [Amigo]  regulation of small GTPase mediated signal transduction
BIOCARTA	Chromatin Remodeling by hSWI/SNF ATP-dependent Complexes    [Genes]
KEGG	MAPK signaling pathway
PubGene	NF1
TreeFam	NF1
CTD	4763 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	NF1 Related clones (RZPD - Berlin)
	PubMed
PubMed	181 Pubmed reference(s) in Entrez

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)

Written	09-1997	Jean-Loup Huret
Updated	02-2006	Katharina 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Sat Oct 11 12:54:23 2008