NF1 (neurofibromin 1)

2006-02-01   Katharina Wimmer 

Medizinische Universitüt Wien, Institut für Humangenetik, Klinischen Instituts für Medizinische und Chemische Labordiagnostik (KIMCL), Wühringerstrasse 10, 1090 Wien, è_sterreich, Austria

Identity

HGNC
LOCATION
17q11.2
LOCUSID
ALIAS
NFNS,VRNF,WSS
FUSION GENES

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

Proteins

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 its GAP activity.

Implicated in

Entity name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
17705311991Watson syndrome: is it a subtype of type 1 neurofibromatosis?Allanson JE et al
90124031997A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors.Cappione AJ et al
21142201990A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations.Cawthon RM et al
163809192005NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.De Luca A et al
152575182004High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene.Kehrer-Sawatzki H et al
147229142004Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene.Kluwe L et al
84999451993Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis.Legius E et al
77749601995Genomic organization of the neurofibromatosis 1 gene (NF1).Li Y et al
108620842000Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.Messiaen LM et al
75956471995Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I.Metheny LJ et al
114317042001Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas.Serra E et al
83023411994Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders.Shannon KM et al
83175031993Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.Tassabehji M et al
16947271990Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.Viskochil D et al
21347341990Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients.Wallace MR et al
162836212006Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients.Wimmer K et al

Other Information

Locus ID:

NCBI: 4763
MIM: 613113
HGNC: 7765
Ensembl: ENSG00000196712

Variants:

dbSNP: 4763
ClinVar: 4763
TCGA: ENSG00000196712
COSMIC: NF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000196712ENST00000356175P21359
ENSG00000196712ENST00000358273P21359
ENSG00000196712ENST00000422121K7EJE7
ENSG00000196712ENST00000431387P21359
ENSG00000196712ENST00000456735H0Y465
ENSG00000196712ENST00000466819J3QQN8
ENSG00000196712ENST00000468273K7EID4
ENSG00000196712ENST00000471572J3QSG6
ENSG00000196712ENST00000479536K7ENT2
ENSG00000196712ENST00000479614J3KRT8
ENSG00000196712ENST00000487476P21359
ENSG00000196712ENST00000490416A0A1W2PPA7
ENSG00000196712ENST00000495910J3QLS2
ENSG00000196712ENST00000579081J3KSB5
ENSG00000196712ENST00000581113A0A1W2PS74
ENSG00000196712ENST00000581790J3KSX8

Expression (GTEx)

0
5
10
15
20

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
MAPK signaling pathwayKEGGhsa04010
Ras signaling pathwayKEGGhsa04014
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Regulation of RAS by GAPsREACTOMER-HSA-5658442
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinasesREACTOMER-HSA-8849471
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
RET signalingREACTOMER-HSA-8853659
Oncogenic MAPK signalingREACTOMER-HSA-6802957
Signaling by RAS mutantsREACTOMER-HSA-6802949
RAS signaling downstream of NF1 loss-of-function variantsREACTOMER-HSA-6802953

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
201292512010Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.2371
232884082013A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition.131
120773392002Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation.112
262145902015Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.105
106251712000NF1 gene and neurofibromatosis 1.93
171609012007An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation.89
245768302014Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.88
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
231717962013Elucidating distinct roles for NF1 in melanomagenesis.83
206554652010NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome.74

Citation

Katharina Wimmer

NF1 (neurofibromin 1)

Atlas Genet Cytogenet Oncol Haematol. 2006-02-01

Online version: http://atlasgeneticsoncology.org/gene/134/nf1

Historical Card

1997-09-01 NF1 (neurofibromin 1) by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France