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{{Infobox_gene}}
{{Infobox_gene}}
'''Neurofibromin 1''' ('''''NF1''''') is a gene in humans that codes for neurofibromin, a [[GTPase-activating protein]] that negatively regulates [[RAS/MAPK pathway]] activity<ref name=":0">{{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-bound [[Guanosine triphosphate|GTP]], leading to the inactivation of Ras.<ref name=":1">{{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=":7">Scheffzek K., Welti S. (2012) Neurofibromin: Protein Domains and Functional Characteristics. In: Upadhyaya M., Cooper D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg</ref> Mutations in ''NF1'' affecting GTPase activity 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=":0" /> Complications include cutaneous [[Neurofibroma|neurofibromas]], [[Café au lait spot|café au lait pigment spots]], [[Plexiform neurofibroma|plexiform neurofibromas]], skeletal defects and [[Optic nerve glioma|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><ref name=":0" />
'''Neurofibromin 1''' ('''''NF1''''') is a gene in humans that 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-bound [[Guanosine triphosphate|GTP]], leading to the inactivation of Ras.<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> Mutations in ''NF1'' affecting GTPase activity 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" /> Complications include cutaneous [[Neurofibroma|neurofibromas]], [[Café au lait spot|café au lait pigment spots]], [[Plexiform neurofibroma|plexiform neurofibromas]], 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 ==
== Gene ==
''NF1'' encodes the protein neurofibromin, a GTPase-activating protein, which primarily regulates the protein [[RAS p21 protein activator 1|Ras]].<ref name=":1" /> ''NF1'' is located on the long arm of [[Chromosome 17 (human)|chromosome 17]], position q11.2<ref name=":0" /> and was identified in 1990 through [[Genetic screen|positional cloning.]]<ref name=":1" /> ''NF1'' spans over 350-kb of [[genomic DNA]] and contains 62 [[Exon|exons.]]<ref name=":2">{{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=":2" /> The genomic sequence starts 4,951-bp upstream of the [[transcription start site]] and 5,334-bp upstream of the translation initiation codon, with the length of the [[Five prime untranslated region|5’ UTR]] being 484-bp long.<ref name=":3">Li H., Wallace M.R. (2012) NF1 Gene: Promoter, 5′ UTR, and 3′ UTR. In: Upadhyaya M., Cooper D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg</ref>
''NF1'' encodes the protein neurofibromin, a GTPase-activating protein, which primarily regulates the protein [[RAS p21 protein activator 1|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 cloning.]]<ref name="Abramowicz_2014" /> ''NF1'' spans over 350-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-bp upstream of the [[transcription start site]] and 5,334-bp upstream of the 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=":3" /> ''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=":1" /> ''OMG'' is a [[membrane glycoprotein]] that is expressed in the human [[central nervous system]] during [[myelination]] of [[nerve cells|nerve cells.]]<ref name=":3" />
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|nerve cells.]]<ref name="Li_2012" />


=== Promoter ===
=== Promoter ===
Early studies of the ''NF1'' [[Promoter (genetics)|promoter]] found that there is great homology between the human and mouse ''NF1'' promoters.<ref name=":3" /> The major transcription start site has been confirmed, as well as well as two minor transcription start sites in both the human and mouse gene.<ref name=":3" />
Early studies of the ''NF1'' [[Promoter (genetics)|promoter]] found that there is great homology between the human and mouse ''NF1'' promoters.<ref name="Li_2012" /> The major transcription start site has been confirmed, as well 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=":4">{{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=":4" /> The ''NF1'' exon 1 is 544-bp long and it contains the 5’ UTR and encodes the first 20 [[Amino acid|amino acids]] of neurofibromin.<ref name=":3" /> The ''NF1'' promoter lies within a [[CpG-island|CpG island]] that is 472-bp long, consisting of 43 [[CpG dinucleotide|CpG dinucleotides]], and extends into the start of exon 1.<ref name=":3" /><ref name=":4" /> 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=":4" /> 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=":3" />
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" /> The ''NF1'' exon 1 is 544-bp long and it contains the 5’ UTR and encodes the first 20 [[Amino acid|amino acids]] 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|CpG dinucleotides]], 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|cytosines]] near the transcription start site were unmethylated.<ref name=":3" />  Methylation has been shown to functionally impact Sp1 sites as well as a [[CREB]] binding site.<ref name=":5">{{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=":5" />
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|cytosines]] near the transcription start site were unmethylated.<ref name="Li_2012" />  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|somatic mutation.]]<ref name=":3" /> There are some sites that have been detected to be methylated at a higher frequency in tumor tissues than normal tissues.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=":3" />
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|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.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 ===
=== 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=":3" /> 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=":3" /> 
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 posttranscriptional gene regulation had an effect on the variation of ''NF1'' transcript quantity both spatially and temporally.<ref name=":3" /> Five regions of the 3’ UTR that appear to bind proteins were found, one of which is HuR, a [[tumor antigen]]<ref name=":6">{{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=":6" /> This supports the idea that posttranscriptional mechanisms may influence the levels of ''NF1'' transcript.<ref name=":6" />
A study conducted in 2000, examined whether the involvement of the 3’ UTR in posttranscriptional 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 posttranscriptional mechanisms may influence the levels of ''NF1'' transcript.<ref name="Haeussler_2000" />


=== Mutations ===
=== Mutations ===
''NF1'' has one of the highest mutation rates amongst known human genes<ref name=":8">Baralle M., Baralle D. (2012) Splicing Mechanisms and Mutations in the NF1 Gene. In: Upadhyaya M., Cooper D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg</ref>, however mutation detection is difficult because of its large size, the presence of [[Pseudogene|pseudogenes]], 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 = PMC4909605 | 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. Approximately 50% of mutations associated with [[Neurofibromatosis type I|neurofibromatosis type 1]] are ''de novo.''<ref name=":1" /> 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=":1" />
''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|pseudogenes]], 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 = PMC4909605 | 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. Approximately 50% of mutations associated with [[Neurofibromatosis type I|neurofibromatosis type 1]] are ''de novo.''<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=":3" /> 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|phenotype.]]<ref name=":3" />
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|phenotype.]]<ref name="Li_2012" />


There have been mutations identified that affect [[splicing]], in fact 286 of the known mutations are identified as splicing mutations.<ref name=":8" /> About 78% of splicing mutations directly affect [[Splice site|splice sites]], which can cause aberrant splicing to occur.<ref name=":8" /> Aberrant splicing may also occur due to mutations within a [[splicing regulatory element]]. Intronic mutations that fall outside of splice sites also fall under splicing mutations, and approximately 5% of splicing mutations are of this nature.<ref name=":8" /> [[Point mutation|Point mutations]] 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=":1" /> 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=":1" />
There have been mutations identified that affect [[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|splice sites]], which can cause aberrant splicing to occur.<ref name="Baralle_2012" /> Aberrant splicing may also occur due to mutations within a [[splicing regulatory element]]. Intronic 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|Point mutations]] 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 ==
== Protein ==
''NF1'' encodes neurofibromin, which is a 320-kDa protein that contains 2,818 amino acids.<ref name=":0" /> Neurofibromin is a [[GTPase-activating protein]] (GAP) that negatively regulates [[Ras pathway]] activity<ref name=":0" /> by accelerating [[hydrolysis]] of Ras-bound [[guanosine triphosphate]] (GTP).<ref name=":7" /> Neurofibromin localizes in the [[cytoplasm]], however some studies have found neurofibromin or fragments of it in the [[nucleus|nucleus.]]<ref name=":7" /> 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=":2" /> Neurofibromin is [[ubiquitously]] expressed, but expression levels vary depending on the tissue type and developmental stage of the organism.<ref name=":0" /> Expression is at its highest level in adult [[Neuron|neurons]], [[Schwann cell|Schwann cells]], [[Astrocyte|astrocytes]], [[leukocytes]], and [[Oligodendrocyte|oligodendrocytes.]]<ref name=":2" /><ref name=":7" />
''NF1'' encodes neurofibromin, which is a 320-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 [[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|neurons]], [[Schwann cell|Schwann cells]], [[Astrocyte|astrocytes]], [[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=":7" /> The GRD is closely homologous to p120GAP<ref name=":7" /> and represents about 10% (229 amino acids<ref name=":7" />) of the neurofibromin sequence.<ref name=":0" /> 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=":7" /> 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=":7" />
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 p120GAP<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=":7" /> 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=":7" /> 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=":7" /> 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=":7" />
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 ===
=== Function ===
Line 44: Line 44:


=== Isoforms ===
=== 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=":2" /> These five isoforms are expressed in distinct tissues and are each detected by specific antibodies.<ref name=":2" />
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=":2" />
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=":2" /> 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=":2" />
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=":2" />
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=":2" />
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=":2" />
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" />


== Clinical significance ==
== Clinical significance ==

Revision as of 05:46, 30 November 2017

NF1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNF1, NFNS, VRNF, WSS, neurofibromin 1
External IDsOMIM: 613113; MGI: 97306; HomoloGene: 141252; GeneCards: NF1; OMA:NF1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4763

18015

Ensembl

ENSG00000196712

ENSMUSG00000020716

UniProt

P21359

Q04690

RefSeq (mRNA)

NM_000267
NM_001042492
NM_001128147

NM_010897

RefSeq (protein)

NP_000258
NP_001035957
NP_001121619

NP_035027

Location (UCSC)Chr 17: 31.09 – 31.38 MbChr 11: 79.23 – 79.47 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Neurofibromin 1 (NF1) is a gene in humans that codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity[5] by accelerating the hydrolysis of Ras-bound GTP, leading to the inactivation of Ras.[6][7] Mutations in NF1 affecting GTPase activity can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome).[5] Complications include cutaneous neurofibromas, café au lait pigment spots, plexiform neurofibromas, skeletal defects and optic nerve gliomas.[8][5]

Gene

NF1 encodes the protein neurofibromin, a GTPase-activating protein, which primarily regulates the protein Ras.[6] NF1 is located on the long arm of chromosome 17, position q11.2[5] and was identified in 1990 through positional cloning.[6] NF1 spans over 350-kb of genomic DNA and contains 62 exons.[9] 58 of these exons are constitutive and 4 exhibit alternative splicing ( 9a, 10a-2, 23a, and 28a).[9] The genomic sequence starts 4,951-bp upstream of the transcription start site and 5,334-bp upstream of the translation initiation codon, with the length of the 5’ UTR being 484-bp long.[10]

There are three genes that are present within intron 27b of NF1. These genes are EVI2B, EVI2A and OMG, which are encoded on the opposite strand and are transcribed in the opposite direction of NF1.[10] EVI2A and EVI2B are human homologs of the Evi-2A and Evi-2B genes in mice that encode proteins related to leukemia in mice.[6] OMG is a membrane glycoprotein that is expressed in the human central nervous system during myelination of nerve cells.[10]

Promoter

Early studies of the NF1 promoter found that there is great homology between the human and mouse NF1 promoters.[10] The major transcription start site has been confirmed, as well as well as two minor transcription start sites in both the human and mouse gene.[10]

The major transcription start is 484-bp upstream of the translation initiation site.[11] The open reading frame is 8,520-bp long and begins at the translation initiation site.[11] The NF1 exon 1 is 544-bp long and it contains the 5’ UTR and encodes the first 20 amino acids of neurofibromin.[10] The NF1 promoter lies within a CpG island that is 472-bp long, consisting of 43 CpG dinucleotides, and extends into the start of exon 1.[10][11] This CpG Island begins 731-bp upstream of the promoter and no core promoter element, such as a TATA or CCATT box, has been found within it.[11] Although no core promoter element has been found, consensus binding sequences have been identified in the 5’ UTR for several transcription factors such as Sp1 and AP2.[10]

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 cytosines near the transcription start site were unmethylated.[10]  Methylation has been shown to functionally impact Sp1 sites as well as a CREB binding site.[12] 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.[12]

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.[10] There are some sites that have been detected to be methylated at a higher frequency in tumor tissues than normal tissues.These sites are mostly within the 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.[10]

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.[10] It was verified that there are two NF1 polyadenylated transcripts that differ in size because of the length of the 3’ UTR, which is consistent with what has been found in the mouse gene.[10] 

A study conducted in 2000, examined whether the involvement of the 3’ UTR in posttranscriptional gene regulation had an effect on the variation of NF1 transcript quantity both spatially and temporally.[10] Five regions of the 3’ UTR that appear to bind proteins were found, one of which is HuR, a tumor antigen[13]. HuR binds to AU-rich elements which are scattered throughout the 3' UTR and are thought to be negative regulators of transcript stability.[13] This supports the idea that posttranscriptional mechanisms may influence the levels of NF1 transcript.[13]

Mutations

NF1 has one of the highest mutation rates amongst known human genes[14], however mutation detection is difficult because of its large size, the presence of pseudogenes, and the variety of possible mutations.[15] The NF1 locus has a high incidence of de novo mutations, meaning that the mutations are not inherited maternally or paternally. Approximately 50% of mutations associated with neurofibromatosis type 1 are de novo.[6] 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.[6]

The Human Gene Mutation Database contains 1,347 NF1 mutations, but none are in the “regulatory” category.[10] 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.[10]

There have been mutations identified that affect splicing, in fact 286 of the known mutations are identified as splicing mutations.[14] About 78% of splicing mutations directly affect splice sites, which can cause aberrant splicing to occur.[14] Aberrant splicing may also occur due to mutations within a splicing regulatory element. Intronic mutations that fall outside of splice sites also fall under splicing mutations, and approximately 5% of splicing mutations are of this nature.[14] Point mutations 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.[6] 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.[6]

Protein

NF1 encodes neurofibromin, which is a 320-kDa protein that contains 2,818 amino acids.[5] Neurofibromin is a GTPase-activating protein (GAP) that negatively regulates Ras pathway activity[5] by accelerating hydrolysis of Ras-bound guanosine triphosphate (GTP).[7] Neurofibromin localizes in the cytoplasm, however some studies have found neurofibromin or fragments of it in the nucleus.[7] Neurofibromin does contain a nuclear localization signal that is encoded by exon 43, but whether or not neurofibromin plays a role in the nucleus is currently unknown.[9] Neurofibromin is ubiquitously expressed, but expression levels vary depending on the tissue type and developmental stage of the organism.[5] Expression is at its highest level in adult neurons, Schwann cells, astrocytes, leukocytes, and oligodendrocytes.[9][7]

The catalytic RasGAP activity of neurofibromin is located in a central portion of the protein, that is called the GAP-related domain (GRD).[7] The GRD is closely homologous to p120GAP[7] and represents about 10% (229 amino acids[7]) of the neurofibromin sequence.[5] 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 residues from the N- and C- terminus.[7] 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.[7]

In addition to the GRD, neurofibromin also contains a Sec14 homology-like region as well as a pleckstrin homology-like (PH) domain.[7] 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.[7] The PH-like region displays a protrusion that connects two beta-strands from the PH core that extend to interact with the helical lid found in the Sec14 domain.[7] 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.[7]

Function

NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the ras signal transduction pathway. Neurofibromin is produced in many types of cells, including nerve and specialized cells such as the oligodendrocytes and also the Schwann cells surrounding the nerve cells. These cells are involved in the formation of myelin sheaths, which are the coverings of certain nerve cells which insulate and protect them.[16]

NF1 is found within the mammalian postsynapse, where it is known to bind to the NMDA receptor complex. It has been found to lead to learning deficits, and it is suspected that this is a result of its regulation of the Ras pathway. It is known to regulate the GTPase HRAS, causing the hydrolyzation of GTP and thereby inactivating it.[17] Within the synapse HRAS is known to activate Src, which itself phosphorylates GRIN2A, leading to its inclusion in the synaptic membrane.

NF1 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 NF1 has a role in the transportation of the NMDA receptor subunits to the synapse and its membrane. NF1 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.[17]

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.[9] These five isoforms are expressed in distinct tissues and are each detected by specific antibodies.[9]

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.[9]

Neurofibromin type 3 (also called isoform 3’ ALT) contains exon 48a which results in the insertion of 18 amino acids into the 3’ terminal.[9] 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.[9]

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.[9]

An isoform with insertion of exon 10a-2 has been studied introduces a transmembrane domain.[18] 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.[9]

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.[9]

Clinical significance

Mutations linked to neurofibromatosis type 1 led to the identification of the NF1 gene. The neurofibromin gene may be mutated in thousands of ways, resulting in many possible clinical outcomes.[19] In addition to neurofibromatosis type I, mutations in NF1 can also lead to juvenile myelomonocytic leukemia, Watson syndrome,[20] and breast cancer.[21] Types of mutations include frameshift, nonsense, missense, splicing alteration and deletion mutations, and loss of heterozygosity.[22][23][24][25]

RNA editing

NF1 mRNA editing can modify disease in humans.[26][27]

Type

The type of editing is a cytidine to uridine (C to U) site specific deamination. The editing site in NF1 mRNA was determined to have a high homology to the ApoB editing site where double stranded mRNA undergoes editing by the ApoB holoenzyme.[28] This alluded to the same holoenzyme involved in ApoB mRNA editing maybe involved in editing of NF1.[29] There are at least four different alternatively spliced forms of the protein, two of which are better defined. They differ by the inclusion of exon 23A. Recent experiments have shown that apobec-1 is indeed expressed outside the gastrointestinal luminal tract in some tumors and the inclusion of downstream exon 23a is preferentially found in these edited transcripts. These two features distinguishes them from tumors where RNA editing does not occur.[30]

Location

The NF1 gene is located on long arm of chromosome 17 at position 11.2(17q11.2).[31] The cytidine in the arginine codon (CGA) is deaminated to a uracil creating an inframe translational stop codon. The editing site is located at nucleotide position 2914. A region (nucleotides 2909-2930) was found to have a high homology to that found in the 21 nucleotide editing region of ApoB mRNA. It was suggested that the same editsome involved in ApoB mRNA editing may also be involved in NF1 mRNA editing. However the 6 nucleotide stretch from the edited cytidine and the start of the mooring sequence is two nucleotides longer than the ideal sequence required for ApoB mRNA editing. Also the region contains 2 guanidines which would be tolerated but again would not be ideal for ApoB mRNA editing. The mooring sequence and regulatory sequence are thought to be sufficient for editing to occur by ApoB mRNA editing machinery. This was determined by site mutagenesis experiments.[32]

Regulation

NF1 RNA editing is not regulated by limited amounts of APOBEC-1. This implies that different factors are involved in NF1 mRNA editing than those associated with ApoB RNA editing. It is thought that different trans acting factors may be involved in the two editing processes.[28] Also, the region surrounding the editing region in NF1 mRNA is GC rich instead of the preferred AT rich sequence found in ApoB mRNA editing site. This reason as well as the longer spacer element of NF1 mRNA than that of ApoB mRNA are thought to be factors in the difference in frequency of editing of the two mRNAs (20% NF1, 90% ApoB).[33] Editing occurs in a higher frequency in tumours compared to the relative normal tissues.[28] There is a higher frequency of editing in the NF1 mRNA which includes Exon 23A in tumors.[30]

Conservation

The editing site is thought not to be conserved as editing of NF1 mRNA does not occur in the rat or mouse but these species do express several alternatively spliced mRNAs.[28][34] One of these alternatively spliced isoforms known as TYPE III in rats and mice introduces a frameshift that introduces a stop codon by inclusion of a 41 base pair exon.[27]

Consequences

Structure

Editing results in a codon change from an arginine codon (CGA) to an in frame stop codon (UGA) due to a base change at nucleotide 2914. The introduction of an inframe stop codon results in a translated protein that is truncated. The translated protein is thought to be lacking its GAP Related Domain (GRD) that shares a homology to mammalian GTPase activating (GAP) domain and yeast inhibitor of RAS protein 1 and 2 domains.[28]

Function

The gene product is neurofibromin, a tumor-suppressor, a region of which functions as a GTPase-activating protein shown to be involved in negative regulation of the RAS pathway.[27][35] NF1 mRNA editing has been detected in a wide range of tissues. Editing results in a truncated protein being translated that does not contain this region. The GTPase region has a high homology to mammalian and yeast (GAPs) which would suggest that neurofibromin plays a role in negative regulation of RAS signal transduction pathways. It is thought that editing therefore would result in the loss of the protein's tumor suppressor activity.[26][36][37] This corresponds to the observed increase in editing in tumors compared to normal tissue, however further research into the role of mRNA editing of NF1 mRNA in pathogenesis in tumours needs to be undertaken.[28][34] There is a correlation in an increase of editing in some tumors and the degree of malignancy of the tumor suggesting a relationship between the two.[27] Recently further evidence of the role of editing in pathogenesis in tumors.It was observed that C to U editing of NF1 mRNA occurs in a fraction of tumor samples of NF1 patients where APOBEC-1 is also expressed. This was an important find as was the first time APOBEC-1 expression was proven experimentally outside the luminal cells of the tract.[30] The N-terminus of the protein has a region demonstrated to be able to bind microtubules. It has been suggested that since the edited protein still retains this region, that a function of this editing is to displace microtubules from the ffull-lengthneurofiromin protein. This would liberate the full-length protein to interact with RAS.[34][38]

Neurofibromatosis

It is thought that RNA editing may account for the wide variation in phenotype of this condition even among siblings.[39] Also, 50% of new cases have new mutations. The frequency is too high to explain these cases as spontaneous mutations, therefore RNA editing of NF1 rna may provide an alternative reason for the variation of phenotype.[29] More than 1000 NF1 mutations that cause neurofibromatosis type 1 have been identified and some belonging to certain families of classification.Research indicates that the formation of neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. Mast cells are normally involved in wound healing and tissue repair.

Model organisms

Model organisms have been used in the study of NF1 function. A conditional knockout mouse line, called Nf1tm1a(KOMP)Wtsi[46][47] 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.[48][49][50]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[44][51] Twenty six tests were carried out on mutant mice and four significant abnormalities were observed.[44] 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.[44]

See also

References

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020716 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d e f g h Peltonen S, Kallionpää RA, Peltonen J (July 2017). "Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas". Experimental Dermatology. 26 (7): 645–648. doi:10.1111/exd.13212. PMID 27622733.
  6. ^ a b c d e f g h Abramowicz A, Gos M (July 2014). "Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease". Developmental Period Medicine. 18 (3): 297–306. PMID 25182393.
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  30. ^ a b c Mukhopadhyay D, Anant S, Lee RM, Kennedy S, Viskochil D, Davidson NO (January 2002). "C-->U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme". American Journal of Human Genetics. 70 (1): 38–50. doi:10.1086/337952. PMC 384902. PMID 11727199.
  31. ^ "NF1 neurofibromin 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 5 July 2016.
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Further reading

External links

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