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FLASH GENE

Symbol

NF1

contributors: mct - updated : 30-08-2016

HGNC name	neurofibromin 1
HGNC id	7765

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

DNA

TYPE	functioning gene
SPECIAL FEATURE	opposite orientation
text	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

RNA

TRANSCRIPTS	type	messenger

text

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)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed variant 4 - splicing - isoform 4 - - 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 variant 6 - splicing - isoform 6 - - in muscle, cardiac and skeleton 2006 16813595 also called NF1 3 or 3-prime ALT containing exon 48a variant 7 - splicing - isoform 7 - - in muscle, cardiac and skeleton 2006 16813595 also called NF1 4 containing both exons 23a and 48a variant 8 - splicing - isoform 8 - - limited neuronal expression 2006 16813595 also called NF1 9a or 9br inclusion of exon 9a involved in the learning and memory mechanisms variant 5 - splicing - isoform 5 - - 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 NM_000267 57 - 12331 NP_000258 316.9 2818 - 2008 18503770 variant 2 lacking an in-frame exon, compared to variant 1 NM_001042492 58 - 12394 NP_001035957 319 2839 - 2008 18503770 variant 1 NM_001128147 15 - 2889 NP_001121619 - 593 - 2008 18503770

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth       moderately   salivary gland       highly Endocrine parathyroid       highly   thyroid       highly Hearing/Equilibrium ear       highly Lymphoid/Immune thymus       moderately Reproductive male system testis     highly Respiratory respiratory tract larynx     moderately Urinary bladder       highly Visual eye       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone     moderately Nervous central     highly

cells

System Cell Pubmed Species Stage Rna symbol Nervous astrocyte Nervous neuron Nervous oligodendrocyte

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	developmental and tissue specific regulation of expression

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	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

HOMOLOGY

interspecies

homolog to rattus Nf1 (98.62 pc)

intraspecies

homolog to Ras GTPase activating protein

Homologene

FAMILY

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleolus

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

PHYSIOLOGICAL PROCESS

development

text	organization of cytoskeleton during the formation of cellular contact

PATHWAY

metabolism

signaling

signal transduction

RTK pathway

a component

INTERACTION

DNA

RNA

small molecule

protein	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

REGULATION

Other

negatively regulated by FAF2

ASSOCIATED DISORDERS

corresponding disease(s)

NF1 , NFNS , WATS , NFFS , NF1DEL

related resource

Neurofibromatosis Type I

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed mental retardation other   decrease GABA-mediated inhibition will be useful for treatment of the learning deficits associated with NF1 cancer brain glioma/neuroblstoma 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 osteoarticular bone   inhibiting MTOR may represent a viable strategy to treat NF1 bone diseases

ANIMAL & CELL MODELS

mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I