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Symbol NF1 contributors: mct - updated : 30-08-2016
HGNC name neurofibromin 1
HGNC id 7765
Corresponding disease
NF1 neurofibromatosis 1 (von Recklinghausen disease)
NF1DEL neurofibromatosis type 1 (see NF1) caused by microdeletions in 17q11.2
NFFS neurofibriomatosis, familial spinal
NFNS Noonan-neurofibromatosis syndrome
WATS Watson syndrome
Location 17q11.2      Physical location : 29.421.944 - 29.704.694
Synonym name
  • neurofibromin
  • neurofibromatosis-related protein NF-1
  • Synonym symbol(s) VRNF, WSS, NFNS, FLJ21220, DKFZp686J1293
    TYPE functioning gene
    SPECIAL FEATURE opposite orientation
  • EVIA, EVIB, OGMP, embedded in intron 27b (see symbols)
  • a NF1 RNA editing C>U in the GRD domain resulting in a truncated form
  • STRUCTURE 282.70 kb     58 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure a cryptic exon situated between exons 4a and 4b, inserted in the NF1 mRNA after a cold shock, also a mRNA editing site in exon 23 creating an in-frame codon stop
    MAPPING cloned Y linked Y status confirmed
    Map cen - D17S841 - D17S975 - D17S1549 - D17S1294 - SLC6A4 - CPD CPD - D17S2009 - D17S2004 - D17S2120 - NF1 NF1 - D17S1800 - D17S798 - D17S54 - D17S933 - D17S946 - qter
    TRANSCRIPTS type messenger
  • at least four alternatively spliced transcripts, four exons with alternative splicing, exon 9a, 10a-2, 23a, 48a
  • alternative exon 23a falls within the Nf1 GAP domain coding sequence and is tightly regulated in favor of skipping in neurons, and likely exon 23a suppresses the Ras-GAP activity of NF1 (PMID: 24710274)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - splicing - - - Schwann cells 2014 24710274
  • also called NF1 II or GRD2
  • insertion of exon 23a
  • reduced capacity of acting as GAP
  • essential role for the normal brain function
  • regulation of NF1 exon 23a inclusion serves as a mechanism for providing appropriate levels of RAS signaling and may be important in modulating RAS-related neuronal functions
  • - splicing - - - in muscle, cardiac and skeleton 2006 16813595
  • also called NF1 3 or 3-prime ALT
  • containing exon 48a
  • - splicing - - - in muscle, cardiac and skeleton 2006 16813595
  • also called NF1 4
  • containing both exons 23a and 48a
  • - splicing - - - limited neuronal expression 2006 16813595
  • also called NF1 9a or 9br
  • inclusion of exon 9a
  • involved in the learning and memory mechanisms
  • - splicing - - - ubiquitous 2006 16813595
  • also called NF1 10a-2
  • insertion of the alternative exon 10a-2
  • introducing a trans membrane domain, and function in the endoplasmic reticulum
  • 57 - 12331 316.9 2818 - 2008 18503770
  • variant 2
  • lacking an in-frame exon, compared to variant 1
  • 58 - 12394 319 2839 - 2008 18503770
    variant 1
    15 - 2889 - 593 - 2008 18503770
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouth   moderately
     salivary gland   highly
    Endocrineparathyroid   highly
     thyroid   highly
    Hearing/Equilibriumear   highly
    Lymphoid/Immunethymus   moderately
    Reproductivemale systemtestis  highly
    Respiratoryrespiratory tractlarynx  moderately
    Urinarybladder   highly
    Visualeye   moderately
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  moderately
    Nervouscentral  highly
    SystemCellPubmedSpeciesStageRna symbol
    cell lineage
    cell lines
    at STAGE
    physiological period fetal, pregnancy
    Text developmental and tissue specific regulation of expression
  • a nuclear localization signal
  • a cysteine and serine-rich domain/Ras-GTPase activating protein domain (CSRD/RasGAP)
  • a GRD and a putative upstream functional domain forming a cysteine/serine rich region
  • a potential ATP binding site
  • a SEC14 domain
  • three potential PRKA recognition sites
  • a C-terminal domain (CTD), regulating the metaphase to anaphase transition in a MAD2L1-independent fashion
    interspecies homolog to rattus Nf1 (98.62 pc)
    intraspecies homolog to Ras GTPase activating protein
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • GTPase activating protein, modulating cytoskeleton-mediated-processes
  • function as a negative regulator of Ras and required in endothelial cells but do not rule out a simultaneous requirement in the neural crest during cardiac development
  • regulator of RAS-induced signals in primary vascular smooth muscle cells
  • playing a critical role for normal histogenesis during embryologic development and wound healing
  • having a function in the modulation of excitability of sensory neurons
  • having an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities and multiple essential roles in skeletal development and growth
  • plays a crucial role in modulating mesenchymal stem/progenitor cells differentiation into osteoblasts, and the defect in osteoblast differentiation may contribute at least in part to the osseous abnormalities seen in individuals with NF1
  • in inhibitory neurons regulates ERK-dependent phosphorylation of synapsin I and consequently GABA release
  • having a critical role in hypothalamic–pituitary axis function in a Ras-independent fashion
  • may function in the mammalian central nervous system (CNS) by modulating either Ras- or cAMP-dependent pathways
  • required for normal glial and neuronal development involving separable Ras-dependent and cAMP-dependent mechanisms
  • regulates activity-dependent GABA release in prefrontal cortex
  • important molecular regulator of interneuronal activity in the prefrontal cortex and striatum, brain regions critical for working memory performance
  • regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner
  • requirement of neurofibromin for muscle formation and maintenance
  • required for the control of MAPK signaling in various cell types, including cardiac and muscle cells
  • directly regulates osteoclastogenesis through MTOR signaling pathway
  • controls astrocyte growth in an AKT1-dependent, but TSC/RHEB-independent, fashion relevant to gliomagenesis
  • regulates CNS neurite length and growth cone areas in a cAMP/PKA/Rho/ROCK-dependent manner
  • regulatory role for NF1 during epicardial epithelial to mesenchymal transition (EMT)
  • by restraining RAS-ERK1/2 signaling, is a negative regulator of FGFR signaling in differentiating chondrocytes
  • is essential for normal muscle function and survival and are the first to suggest a direct link between NF1 and mitochondrial fatty acid metabolism
  • is the major RAS inactivator in dendritic spines
  • inactivates the oncoprotein RAS and plays important roles in nervous system development and learning
  • likely involved in the regulation of mechanical sensing, bone matrix composition and mechanical resistance of bone tissue
  • NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
  • in prehypertrophic chondrocytes, downstream of FGFR1and FGFR3 and via an indirect mechanism, is required for normal extension and organization of proliferative columns
  • role for NF1 in the melanocyte lineage
  • differentially controls neural stem cell (NSC) proliferation and multilineage differentiation through the selective use of the PI3K/AKT1 and RAF/MEK pathways
  • during mitosis, is an integral part of the spindle, while its depletion leads to aberrant chromosome congression, possibly explaining the development of chromosomal instability in NF1
  • CELLULAR PROCESS cell cycle
    cell life, proliferation/growth
    cell organization/biogenesis
    cell migration & motility
    text organization of cytoskeleton during the formation of cellular contact
    signaling signal transduction
    RTK pathway
    a component
    small molecule
  • RAS (inhibitor of), GAP43, CDH13
  • interacting with the homodimer of SDC2
  • NF1 cooperates with BRAF mutations in melanoma
  • NF1 gene silencing induces upregulation of VEGFA expression in both Schwann and non-Schwann cells
  • DYNC1H1 interact with NF1 along microtubules in vesicular structures identified to be melanosomes and disruptions in the interaction may contribute to the abnormal pigmentary features commonly associated with NF1 disease
  • AKR1C2 (positive factor) and NF1 (negative factor), are the MTDH downstream players in the process of metastasis in liver cancer
  • SPRED1 has previously been demonstrated to interact with NF1 via its N-terminal Ena/VASP Homology 1 (EVH1) domain and to mediate membrane translocation of its target dependent on its C-terminal Sprouty domain
  • cell & other
    Other negatively regulated by FAF2
    corresponding disease(s) NF1 , NFNS , WATS , NFFS , NF1DEL
    related resource Neurofibromatosis Type I
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in NF1 tumor and juvenile myelomonocytic leukemia, in malignant peripheral nerve SHEAT tumors (MPNSTS) (early onset, poor prognosis), in melanoma desmoplastic ,neurotropic
    tumoral       loss of function
    in neurofibroma
    constitutional     --low  
    results in increased Ras activity and downstream MAPK/Akt signaling
    tumoral     --low  
    with ZNF423, in neuroblastomas with poor outcome
    tumoral somatic mutation      
    in gastrointestinal stromal tumors (GISTs)
    tumoral somatic mutation      
    in Desmoplastic Melanoma
    Variant & Polymorphism
    Candidate gene
    Therapy target
    mental retardationother 
    decrease GABA-mediated inhibition will be useful for treatment of the learning deficits associated with NF1
    inhibition of MAP2K1 signaling downstream of NF1 restores responsiveness to Retinoic acid (RA), suggesting a therapeutic strategy to overcome RA resistance in NF1-deficient neuroblastomas
    inhibiting MTOR may represent a viable strategy to treat NF1 bone diseases
  • mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I