View source for Neurofibromin 1

{{Infobox_gene}}
'''Neurofibromin 1''' ('''''NF1''''') is a gene in humans that is located on chromosome 17.<ref name="Peltonen_2017" /> ''NF1'' codes for neurofibromin, a [[GTPase-activating protein]] that negatively regulates [[RAS/MAPK pathway]] activity<ref name="Peltonen_2017">{{cite journal | vauthors = Peltonen S, Kallionpää RA, Peltonen J | title = Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas | journal = Experimental Dermatology | volume = 26 | issue = 7 | pages = 645–648 | date = July 2017 | pmid = 27622733 | doi = 10.1111/exd.13212  }}</ref> by accelerating the [[hydrolysis]] of [[Ras superfamily|Ras]]-bound [[Guanosine triphosphate|GTP]].<ref name="Abramowicz_2014">{{cite journal | vauthors = Abramowicz A, Gos M | title = Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease | journal = Developmental Period Medicine | volume = 18 | issue = 3 | pages = 297–306 | date = July 2014 | pmid = 25182393  }}</ref><ref name="Scheffzek_2012">{{cite book | vauthors = Scheffzek K, Welti S | year = 2012 | chapter = Neurofibromin: Protein Domains and Functional Characteristics | veditors = Upadhyaya M, Cooper D | title = Neurofibromatosis Type 1. | publisher = Springer | location = Berlin, Heidelberg | doi = 10.1007/978-3-642-32864-0_20 | isbn = 978-3-642-32864-0 | pages = 305–326 }}</ref> There are currently five known neurofibromin [[isoforms]] that are expressed in different tissues and perform different functions.<ref name="Trovó-Marqui_2006" /> ''NF1'' has a high mutation rate and mutations in ''NF1'' can alter cellular growth control, and neural development, resulting in [[Neurofibromatosis type I|neurofibromatosis type 1]] (NF1, also known as von Recklinghausen syndrome).<ref name="Peltonen_2017" /> Symptoms of NF1 include [[cutaneous]] [[neurofibroma]]s, [[Café au lait spot|café au lait pigment spots]], [[plexiform neurofibroma]]s, skeletal defects and [[Optic nerve glioma|optic nerve gliomas.]]<ref>{{cite book | vauthors = Peltonen S, Pöyhönen M | year = 2012 | chapter = Clinical Diagnosis and Atypical Forms of NF1 | veditors = Upadhyaya M, Cooper D | title = Neurofibromatosis Type 1. | publisher = Springer | location = Berlin, Heidelberg | doi = 10.1007/978-3-642-32864-0_2 | isbn = 978-3-642-32864-0 | pages = 17–30 }}</ref><ref name="Peltonen_2017" />

== Gene ==
''NF1'' encodes the protein neurofibromin, a GTPase-activating protein, which primarily regulates the protein Ras.<ref name="Abramowicz_2014" /> ''NF1'' is located on the long arm of [[Chromosome 17 (human)|chromosome 17]], position q11.2<ref name="Peltonen_2017" /> and was identified in 1990 through [[Genetic screen|positional&nbsp;cloning.]]<ref name="Abramowicz_2014" /> ''NF1'' spans over 350-[[Kilobase|kb]] of [[genomic DNA]] and contains 62 [[Exon|exons.]]<ref name="Trovó-Marqui_2006">{{cite journal | vauthors = Trovó-Marqui AB, Tajara EH | title = Neurofibromin: a general outlook | journal = Clinical Genetics | volume = 70 | issue = 1 | pages = 1–13 | date = July 2006 | pmid = 16813595 | doi = 10.1111/j.1399-0004.2006.00639.x  }}</ref> 58 of these exons are constitutive and 4 exhibit [[alternative splicing]] ( 9a, 10a-2, 23a, and 28a).<ref name="Trovó-Marqui_2006" /> The [[genomic sequence]] starts 4,951-[[Base pair|bp]] upstream of the [[transcription start site]] and 5,334-bp upstream of the [[Translation (biology)|translation]] [[initiation codon]], with the length of the [[Five prime untranslated region|5’ UTR]] being 484-bp long.<ref name="Li_2012">{{cite book | vauthors = Li H, Wallace MR | year = 2012 | chapter = NF1 Gene: Promoter, 5′ UTR, and 3′ UTR. | veditors = Upadhyaya M, Cooper D | title = Neurofibromatosis Type 1. | publisher = Springer | location = Berlin, Heidelberg | doi = 10.1007/978-3-642-32864-0_9 | isbn = 978-3-642-32864-0 | pages = 105–113 }}</ref>

There are three genes that are present within [[intron]] 27b of ''NF1''. These genes are ''[[EVI2B]]'', ''EVI2A'' and [[OMG (gene)|''OMG'',]] which are encoded on the opposite strand and are transcribed in the opposite direction of ''NF1.''<ref name="Li_2012" /> ''EVI2A'' and ''EVI2B'' are human homologs of the ''Evi-2A'' and ''Evi-2B'' genes in mice that encode proteins related to [[leukemia]] in mice.<ref name="Abramowicz_2014" /> ''OMG'' is a [[membrane glycoprotein]] that is expressed in the human [[central nervous system]] during [[myelination]] of [[nerve cells]].<ref name="Li_2012" />

=== Promoter ===
Early studies of the ''NF1'' [[Promoter (genetics)|promoter]] found that there is great [[Homology (biology)|homology]] between the human and mouse ''NF1'' promoters.<ref name="Li_2012" /> The major transcription start site has been confirmed, as well as two minor transcription start sites in both the human and mouse gene.<ref name="Li_2012" />

The major transcription start is 484-bp upstream of the translation initiation site.<ref name="Lee_2005">{{cite journal | vauthors = Lee TK, Friedman JM | title = Analysis of NF1 transcriptional regulatory elements | journal = American Journal of Medical Genetics. Part A | volume = 137 | issue = 2 | pages = 130–5 | date = August 2005 | pmid = 16059932 | doi = 10.1002/ajmg.a.30699  }}</ref> The [[open reading frame]] is 8,520-bp long and begins at the translation initiation site.<ref name="Lee_2005" /> ''NF1'' exon 1 is 544-bp long, contains the 5’ UTR and encodes the first 20 [[amino acid]]s of neurofibromin.<ref name="Li_2012" /> The ''NF1'' promoter lies within a [[CpG-island|CpG island]] that is 472-bp long, consisting of 43 [[CpG dinucleotide]]s, and extends into the start of exon 1.<ref name="Li_2012" /><ref name="Lee_2005" /> This CpG Island begins 731-bp upstream of the promoter and no core promoter element, such as a [[TATA box|TATA]] or [[CCAAT box|CCATT]] box, has been found within it.<ref name="Lee_2005" /> Although no core promoter element has been found, [[Consensus sequence|consensus]] binding sequences have been identified in the 5’ UTR for several [[Transcription factors, general|transcription factors]] such as [[Sp1 transcription factor|Sp1]] and AP2.<ref name="Li_2012" />

A [[methylation]] map of five regions of the promoter in both mouse and human was published in 1999. This map showed that three of the regions (at approximately – 1000, – 3000, and – 4000) were frequently methylated, but the [[cytosine]]s near the transcription start site were unmethylated.<ref name="Li_2012" />&nbsp; Methylation has been shown to functionally impact Sp1 sites as well as a [[CREB]] binding site.<ref name="Zou_2004">{{cite journal | vauthors = Zou MX, Butcher DT, Sadikovic B, Groves TC, Yee SP, Rodenhiser DI | title = Characterization of functional elements in the neurofibromatosis (NF1) proximal promoter region | journal = Oncogene | volume = 23 | issue = 2 | pages = 330–9 | date = January 2004 | pmid = 14647436 | doi = 10.1038/sj.onc.1207053  }}</ref> It has been shown that the CREB site must be intact for normal promoter activity to occur and methylation at the Sp1 sites may affect promoter activity.<ref name="Zou_2004" />

Proximal ''NF1'' promoter/5’ UTR methylation has been analyzed in tissues from NF1 patients, with the idea that reduced transcription as a result of methylation could be a “second hit” mechanism equivalent to a [[somatic mutation]].<ref name="Li_2012" /> There are some sites that have been detected to be methylated at a higher frequency in tumor tissues than normal tissues.<ref name="Li_2012" /> These sites are mostly within the [[Proximal promoter element|proximal promoter]]; however, some are in the 5’ UTR as well and there is a lot of [[interindividual variability]] in the cytosine methylation in these regions.<ref name="Li_2012" />

=== 3' UTR ===
A study in 1993 compared the mouse ''NF1'' [[cDNA]] to the human transcript and found that both the untranslated regions and coding regions were highly conserved.<ref name="Li_2012" /> It was verified that there are two ''NF1'' [[Polyadenylation|polyadenylated]] transcripts that differ in size because of the length of the [[3'-UTR|3’ UTR]], which is consistent with what has been found in the mouse gene.<ref name="Li_2012" />

A study conducted in 2000 examined whether the involvement of the 3’ UTR in [[Post-transcriptional regulation|post-transcriptional gene regulation]] had an effect on the variation of ''NF1'' transcript quantity both spatially and temporally.<ref name="Li_2012" /> Five regions of the 3’ UTR that appear to bind proteins were found, one of which is [[HuR]], a [[tumor antigen]].<ref name="Haeussler_2000">{{cite journal | vauthors = Haeussler J, Haeusler J, Striebel AM, Assum G, Vogel W, Furneaux H, Krone W | title = Tumor antigen HuR binds specifically to one of five protein-binding segments in the 3'-untranslated region of the neurofibromin messenger RNA | journal = Biochemical and Biophysical Research Communications | volume = 267 | issue = 3 | pages = 726–32 | date = January 2000 | pmid = 10673359 | doi = 10.1006/bbrc.1999.2019  }}</ref> HuR binds to [[Au rich elements|AU-rich elements]] which are scattered throughout the 3' UTR and are thought to be negative regulators of transcript stability.<ref name="Haeussler_2000" /> This supports the idea that post-transcriptional mechanisms may influence the levels of ''NF1'' transcript.<ref name="Haeussler_2000" />

=== Mutations ===
''NF1'' has one of the highest mutation rates amongst known human genes,<ref name="Baralle_2012">{{cite book | vauthors = Baralle M, Baralle D | year = 2012 | chapter = Splicing Mechanisms and Mutations in the NF1 Gene. | veditors = Upadhyaya M, Cooper D | title = Neurofibromatosis Type 1. | publisher = Springer | location = Berlin, Heidelberg | doi = 10.1007/978-3-642-32864-0_11 | isbn = 978-3-642-32864-0 | pages = 135–150 }}</ref> however mutation detection is difficult because of its large size, the presence of [[pseudogene]]s, and the variety of possible mutations.<ref>{{cite journal | vauthors = Pasmant E, Vidaud D | title = Neurofibromatosis Type 1 Molecular Diagnosis: The RNA Point of View | journal = EBioMedicine | volume = 7 | pages = 21–2 | date = May 2016 | pmid = 27322453 | pmc = 4909605 | doi = 10.1016/j.ebiom.2016.04.036  }}</ref> The ''NF1'' locus has a high incidence of [[De novo mutation|''de novo'' mutations]], meaning that the mutations are not inherited maternally or paternally''.''<ref name="Abramowicz_2014" /> Although the mutation rate is high, there are no mutation “hot spot” regions. Mutations tend to be distributed within the gene, although exons 3, 5, and 27 are common sites for mutations.<ref name="Abramowicz_2014" />

The Human Gene Mutation Database contains 1,347 ''NF1'' mutations, but none are in the “regulatory” category.<ref name="Li_2012" /> There have not been any mutations conclusively identified within the promoter or untranslated regions. This may be because such mutations are rare, or they do not result in a recognizable [[phenotype]].<ref name="Li_2012" />

There have been mutations identified that affect [[Genetic engineering|splicing]], in fact 286 of the known mutations are identified as splicing mutations.<ref name="Baralle_2012" /> About 78% of splicing mutations directly affect [[splice site]]s, which can cause aberrant splicing to occur.<ref name="Baralle_2012" /> Aberrant splicing may also occur due to mutations within a [[splicing regulatory element]]. [[Intron]]ic mutations that fall outside of splice sites also fall under splicing mutations, and approximately 5% of splicing mutations are of this nature.<ref name="Baralle_2012" /> [[Point mutation]]s that effect splicing are commonly seen and these are often substitutions in the regulatory sequence. Exonic mutations can lead to deletion of an entire exon, or a fragment of an exon if the mutation creates a new splice site.<ref name="Abramowicz_2014" /> Intronic mutations can result in the insertion of a cryptic exon, or result in [[exon skipping]] if the mutation is in the conserved 3’ or 5’ end.<ref name="Abramowicz_2014" />

== Protein ==
''NF1'' encodes neurofibromin (Nf1), which is a 320-[[Kilodalton|kDa]] protein that contains 2,818 amino acids.<ref name="Peltonen_2017" /> Neurofibromin is a [[GTPase-activating protein]] (GAP) that negatively regulates [[Ras pathway]] activity<ref name="Peltonen_2017" /> by accelerating [[hydrolysis]] of Ras-bound [[guanosine triphosphate]] (GTP).<ref name="Scheffzek_2012" /> Neurofibromin localizes in the [[cytoplasm]]; however, some studies have found neurofibromin or fragments of it in the [[Cell nucleus|nucleus]].<ref name="Scheffzek_2012" /> Neurofibromin does contain a [[Nuclear Localization Signal|nuclear localization signal]] that is encoded by exon 43, but whether or not neurofibromin plays a role in the nucleus is currently unknown.<ref name="Trovó-Marqui_2006" /> Neurofibromin is [[ubiquitously]] expressed, but expression levels vary depending on the tissue type and developmental stage of the organism.<ref name="Peltonen_2017" /> Expression is at its highest level in adult [[neuron]]s, [[Schwann cell]]s, [[astrocyte]]s, [[leukocytes]], and [[Oligodendrocyte|oligodendrocytes.]]<ref name="Trovó-Marqui_2006" /><ref name="Scheffzek_2012" />

The catalytic [[RasGAP]] activity of neurofibromin is located in a central portion of the protein, that is called the GAP-related domain (GRD).<ref name="Scheffzek_2012" /> The GRD is closely homologous to RasGAP<ref name="Scheffzek_2012" /> and represents about 10% (229 amino acids<ref name="Scheffzek_2012" />) of the neurofibromin sequence.<ref name="Peltonen_2017" /> The GRD is made up of a central portion called the minimal central catalytic domain (GAPc) as well as an extra domain (GAPex) that is formed through the coiling of about 50 [[Residue (amino acid)|residues]] from the [[N-terminus|N]]- and [[C-terminus|C]]- terminus.<ref name="Scheffzek_2012" /> The Ras-binding region is found in the surface of GAPc and consists of a shallow pocket that is lined by conserved amino acid residues.<ref name="Scheffzek_2012" />

In addition to the GRD, neurofibromin also contains a [[SEC14L2|Sec14]] homology-like region as well as a [[Pleckstrin homology domain|pleckstrin homology-like (PH) domain.]]<ref name="Scheffzek_2012" /> Sec14 domains are defined by a [[lipid]] [[binding pocket]] that resembles a cage and is covered by a helical lid portion that is believed to regulate [[ligand]] access.<ref name="Scheffzek_2012" /> The PH-like region displays a protrusion that connects two [[Beta strand|beta-strands]] from the PH core that extend to interact with the helical lid found in the Sec14 domain.<ref name="Scheffzek_2012" /> The function of the interaction between these two regions is presently unclear, but the structure implies a regulatory interaction that influences the helical-lid conformation in order to control ligand access to the lipid binding pocket.<ref name="Scheffzek_2012" />

===  Function ===

Through its NF1-GRD domain, neurofibromin increases the rate of GTP hydrolysis of Ras, and acts as a tumor suppressor by reducing Ras activity.<ref name="Trovó-Marqui_2006" /> When the Ras-Nf1 complex assembles, active Ras binds in a groove that is present in the neurofibromin catalytic domain.<ref name="Trovó-Marqui_2006" /> This binding occurs through Ras switch regions I and II, and an arginine finger present in neurofibromin.<ref name="Trovó-Marqui_2006" /> The interaction between Ras and neurofibromin causes GAP-stimulated hydrolysis of GTP to GDP.<ref name="Trovó-Marqui_2006" /> This process depends on the stabilization of residues in the Ras switch I and switch II  regions, which drives Ras into the confirmation required for enzymatic function.<ref name="Trovó-Marqui_2006" /> This interaction between Ras and neurofibromin also requires the transition state of GDP hydrolysis to be stabilized, which is performed through the insertion of the positively charged arginine finger into the Ras active site.<ref name="Trovó-Marqui_2006" /> This neutralizes the negative charges that are present on GTP during phosphoryl transfer.<ref name="Trovó-Marqui_2006" /> By hydrolyzing GTP to GDP, neurofibromin inactivates Ras and therefore negatively regulates the Ras pathway, which controls the expression of genes involved in apoptosis, the cell cycle, cell differentiation or migration.<ref name="Trovó-Marqui_2006" />

Neurofibromin is also known to interact with [[CASK]] through [[syndecan]], a protein which is involved in the KIF17/ABPA1/CASK/LIN7A complex, which is involved in trafficking [[GRIN2B]] to the synapse. This suggests that neurofibromin has a role in the transportation of the NMDA receptor subunits to the synapse and its membrane. Neurofibromin is also believed to be involved in the synaptic ATP-PKA-cAMP pathway, through modulation of [[adenylyl cyclase]]. It is also known to bind the [[caveolin 1]], a protein which regulates p21ras, PKC and growth response factors.<ref name="Trovó-Marqui_2006" />

=== Isoforms ===
There are currently five known [[isoforms]] of neurofibromin (II, 3, 4, 9a, and 10a-2) and these isoforms are generated through the inclusion of  [[alternative splicing]] exons (9a, 10a-2, 23a, and 48a) that do not alter the reading frame.<ref name="Trovó-Marqui_2006" /> These five isoforms are expressed in distinct tissues and are each detected by specific [[antibodies]].<ref name="Trovó-Marqui_2006" />

Neurofibromin type II, also named GRD2 (domain II-related GAP), results from the insertion of exon 23a, which causes the addition of 21 amino acids in the 5’ region of the protein. Neurofibromin type II is expressed in Schwann cells and has reduced GAP activity.<ref name="Trovó-Marqui_2006" />

Neurofibromin type 3 (also called isoform 3’ ALT) contains exon 48a which results in the insertion of 18 amino acids into the 3’ terminal.<ref name="Trovó-Marqui_2006" /> Neurofibromin type 4 contains exons 23a and 48a, which results in the insertion of 21 amino acids in the 5’ region, and 18 amino acids in the 3’ terminal.<ref name="Trovó-Marqui_2006" />

Neurofibromin 9a (also referred to as 9br), includes exon 9a which results in the insertion of 10 amino acids in the 5’ region. This isoform shows little neuronal expression and may play a role in memory and learning mechanisms.<ref name="Trovó-Marqui_2006" />

An isoform with insertion of exon 10a-2 has been studied introduces a transmembrane domain.<ref>{{cite journal | vauthors = Kaufmann D, Müller R, Kenner O, Leistner W, Hein C, Vogel W, Bartelt B | title = The N-terminal splice product NF1-10a-2 of the NF1 gene codes for a transmembrane segment | journal = Biochemical and Biophysical Research Communications | volume = 294 | issue = 2 | pages = 496–503 | date = June 2002 | pmid = 12051738 | doi = 10.1016/S0006-291X(02)00501-6  }}</ref> The inclusion of exon 10a-2 causes the insertion of 15 amino acids in the 5’ region. This isoform is expressed in most human tissues, therefore it likely performs a housekeeping function in intracellular membranes.<ref name="Trovó-Marqui_2006" />

It has been suggested that the quantitative differences in expression between the different isoforms may be related to the phenotypic variability of neurofibromatosis type 1 patients.<ref name="Trovó-Marqui_2006" />

==RNA editing==
In the ''NF1'' [[Messenger RNA|mRNA]], there is a site within the first half of the GRD where mRNA editing occurs.<ref name=":0">{{Cite journal|last=Cappione|first=A. J.|last2=French|first2=B. L.|last3=Skuse|first3=G. R.|date=February 1997|title=A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors|journal=American Journal of Human Genetics|volume=60|issue=2|pages=305–312|issn=0002-9297|pmc=1712412|pmid=9012403}}</ref> [[Deamination]] occurs at this site, resulting in the conversion of [[cytidine]] into [[uridine]] at [[nucleotide]] 3916.<ref name=":0" /><ref name=":1">{{Cite journal|last=Skuse|first=G. R.|last2=Cappione|first2=A. J.|last3=Sowden|first3=M.|last4=Metheny|first4=L. J.|last5=Smith|first5=H. C.|date=1996-02-01|title=The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing|journal=Nucleic Acids Research|volume=24|issue=3|pages=478–485|issn=0305-1048|pmid=8602361|doi=10.1093/nar/24.3.478|pmc=145654}}</ref> This deamination changes an [[arginine]] [[codon]] (CGA) to an in-frame translation [[stop codon]] (UGA).<ref name=":1" /> If the edited transcript is translated, it produces a protein that cannot function as a tumor suppressor because the [[N-terminus|N-terminal]] of the GRD is truncated.<ref name=":0" /> The editing site in ''NF1'' mRNA was shown to have high homology to the [[Apolipoprotein B|ApoB]] editing site, where [[Double-stranded RNA|double stranded mRNA]] undergoes editing by the ApoB [[holoenzyme]].<ref name=":1" /> ''NF1'' mRNA editing was believed to involve the ApoB holoenzyme due to the high homology between the two editing sites, however studies have shown that this is not the case.<ref name=":0" /> The editing site in ''NF1'' is longer than the sequence required for ApoB mediated mRNA editing, and the region contains two [[guanidine]]s which are not present in the ApoB editing site.<ref name=":1" />

== Clinical significance ==

Mutations in ''NF1'' are primarily associated with neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome).<ref name="Peltonen_2017" /> NF1 is the most common [[Single-gene disorder|single gene disorder]] in humans, occurring in about 1 in 2500-3000 births worldwide.<ref>{{Cite journal|last=Woodrow|first=Christopher|last2=Clarke|first2=Anna|last3=Amirfeyz|first3=Rouin|title=Neurofibromatosis|url=https://doi.org/10.1016/j.mporth.2015.02.004|journal=Orthopaedics and Trauma|volume=29|issue=3|pages=206–210|doi=10.1016/j.mporth.2015.02.004|year=2015}}</ref> NF1 is an [[autosomal dominant disorder]], but approximately half of NF1 cases arise from ''de novo'' mutations. NF1 has  high phenotypic variability, with members of the same family with the same mutation displaying different symptoms and symptom intensities.<ref>{{Cite journal|last=Williams|first=Virginia C.|last2=Lucas|first2=John|last3=Babcock|first3=Michael A.|last4=Gutmann|first4=David H.|last5=Korf|first5=Bruce|last6=Maria|first6=Bernard L.|date=January 2009|title=Neurofibromatosis type 1 revisited|journal=Pediatrics|volume=123|issue=1|pages=124–133|doi=10.1542/peds.2007-3204|issn=1098-4275|pmid=19117870}}</ref><ref>{{Cite journal|last=Ward|first=Beth Ann|last2=Gutmann|first2=David H.|date=April 2005|title=Neurofibromatosis 1: from lab bench to clinic|journal=Pediatric Neurology|volume=32|issue=4|pages=221–228|doi=10.1016/j.pediatrneurol.2004.11.002|issn=0887-8994|pmid=15797177}}</ref> Café-au-lait spots are the most common sign of NF1, but other symptoms include [[lisch nodule]]s, cutaneous neurofibromas, plexiform neurofibromas, skeletal defects, and optic nerve gliomas.<ref>Peltonen S., Pöyhönen M. (2012) Clinical Diagnosis and Atypical Forms of NF1. In: Upadhyaya M., Cooper D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg</ref>

In addition to [[neurofibromatosis type I]], mutations in ''NF1'' can also lead to [[juvenile myelomonocytic leukemia]], [[Watson syndrome]],<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4763|title=Entrez Gene: NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease)|accessdate=}}</ref>  and [[breast cancer]].<ref name="nature11412">{{cite journal|author=Cancer Genome Atlas|date=October 2012|title=Comprehensive molecular portraits of human breast tumours|journal=Nature|publisher=Nature Publishing Group|volume=490|issue=7418|pages=61–70|bibcode=2012Natur.490...61T|doi=10.1038/nature11412|pmc=3465532|pmid=23000897}}</ref>

== Model organisms ==

{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
|+ ''Nf1'' knockout mouse phenotype
|-
! Characteristic!! Phenotype
|-
| [[Homozygote]] viability || bgcolor="#C40000"|Abnormal
|-
| [[Recessive]] lethal study || bgcolor="#C40000"|Abnormal
|-
| Fertility || bgcolor="#488ED3"|Normal
|-
| Body weight || bgcolor="#488ED3"|Normal
|-
| [[Open Field (animal test)|Anxiety]] || bgcolor="#488ED3"|Normal
|-
| Neurological assessment || bgcolor="#488ED3"|Normal
|-
| Grip strength || bgcolor="#488ED3"|Normal
|-
| [[Hot plate test|Hot plate]] || bgcolor="#488ED3"|Normal
|-
| [[Dysmorphology]] || bgcolor="#C40000"|Abnormal<ref name="Dysmorphology">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MAHR/dysmorphology/ |title=Dysmorphology data for Nf1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Indirect calorimetry]] || bgcolor="#488ED3"|Normal
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
|-
| [[Auditory brainstem response]] || bgcolor="#488ED3"|Normal
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#488ED3"|Normal
|-
| [[Radiography]] || bgcolor="#488ED3"|Normal
|-
| Body temperature || bgcolor="#488ED3"|Normal
|-
| Eye morphology || bgcolor="#488ED3"|Normal
|-
| [[Clinical chemistry]] || bgcolor="#488ED3"|Normal
|-
| [[Blood plasma|Plasma]] [[immunoglobulin]]s || bgcolor="#488ED3"|Normal
|-
| [[Haematology]] || bgcolor="#488ED3"|Normal
|-
| [[Peripheral blood lymphocyte]]s || bgcolor="#C40000"|Abnormal<ref name="Peripheral blood lymphocytes">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MAHR/peripheral-blood-lymphocytes/ |title=Peripheral blood lymphocytes data for Nf1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Micronucleus test]] || bgcolor="#488ED3"|Normal
|-
| Heart weight || bgcolor="#488ED3"|Normal
|-
| Skin Histopathology || bgcolor="#488ED3"|Normal
|-
| Brain histopathology || bgcolor="#488ED3"|Normal
|-
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Salmonella'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MAHR/salmonella-challenge/ |title=''Salmonella'' infection data for Nf1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MAHR/citrobacter-challenge/ |title=''Citrobacter'' infection data for Nf1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal| doi = 10.1111/j.1755-3768.2010.4142.x| title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice| year = 2010| author = Gerdin AK| journal = Acta Ophthalmologica| volume = 88| issue = S248| pages = 0 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
|}
[[Model organism]]s have been used in the study of NF1 function. A conditional [[knockout mouse]] line, called ''Nf1<sup>tm1a(KOMP)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Nf1 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4364806 |title=Mouse Genome Informatics}}</ref> was generated as part of the [[International Knockout Mouse Consortium]] program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref>

Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | date = June 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref> Twenty six tests were carried out on [[mutant]] mice and four significant abnormalities were observed.<ref name="mgp_reference" /> Over half the [[homozygous]] [[mutant]] embryos identified during gestation were dead, and in a separate study none survived until [[weaning]]. The remaining tests were carried out on [[heterozygous]] mutant adult mice: females displayed abnormal hair cycling while males had an decreased [[B cell]] number and an increased [[monocyte]] cell number.<ref name="mgp_reference" />

== See also ==
* [[SPRED1 gene]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Upadhyaya M, Shaw DJ, Harper PS | title = Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene | journal = Human Mutation | volume = 4 | issue = 2 | pages = 83–101 | year = 1994 | pmid = 7981724 | doi = 10.1002/humu.1380040202 }}
* {{cite journal | vauthors = Shen MH, Harper PS, Upadhyaya M | title = Molecular genetics of neurofibromatosis type 1 (NF1) | journal = Journal of Medical Genetics | volume = 33 | issue = 1 | pages = 2–17 | date = January 1996 | pmid = 8825042 | pmc = 1051805 | doi = 10.1136/jmg.33.1.2 }}
* {{cite journal | vauthors = Feldkamp MM, Gutmann DH, Guha A | title = Neurofibromatosis type 1: piecing the puzzle together | journal = The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques | volume = 25 | issue = 3 | pages = 181–91 | date = August 1998 | pmid = 9706718 | doi =  }}
* {{cite journal | vauthors = Hamilton SJ, Friedman JM | title = Insights into the pathogenesis of neurofibromatosis 1 vasculopathy | journal = Clinical Genetics | volume = 58 | issue = 5 | pages = 341–4 | date = November 2000 | pmid = 11140831 | doi = 10.1034/j.1399-0004.2000.580501.x }}
* {{cite journal | vauthors = Baralle D, Baralle M | title = Splicing in action: assessing disease causing sequence changes | journal = Journal of Medical Genetics | volume = 42 | issue = 10 | pages = 737–48 | date = October 2005 | pmid = 16199547 | pmc = 1735933 | doi = 10.1136/jmg.2004.029538 }}
* {{cite journal | vauthors = Mensink KA, Ketterling RP, Flynn HC, Knudson RA, Lindor NM, Heese BA, Spinner RJ, Babovic-Vuksanovic D | title = Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature | journal = Journal of Medical Genetics | volume = 43 | issue = 2 | pages = e8 | date = February 2006 | pmid = 16467218 | pmc = 2603036 | doi = 10.1136/jmg.2005.034256 }}
* {{cite journal | vauthors = Trovó-Marqui AB, Tajara EH | title = Neurofibromin: a general outlook | journal = Clinical Genetics | volume = 70 | issue = 1 | pages = 1–13 | date = July 2006 | pmid = 16813595 | doi = 10.1111/j.1399-0004.2006.00639.x }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=nf1  GeneReviews/NCBI/NIH/UW entry on Neurofibromatosis 1]
* [http://genome.ucsc.edu/cgi-bin/hgGene?hgg_gene=uc002hgf.1&org=human Human Gene NF1 (uc002hgf.1)]
* [https://www.genecards.org/cgi-bin/carddisp.pl?gene=NF1 neurofibromin 1] from [[GeneCards]]
* [http://darned.ucc.ie Database of RNA editing]

{{PDB Gallery|geneid=4763}}
{{GTP-binding protein regulators}}
{{Tumor suppressor genes}}
{{Use dmy dates|date=January 2012}}

[[Category:Proteins]]
[[Category:Genes mutated in mice]]