Neurofibromin 1
Encyclopedia
Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein
that in humans is encoded by the NF1 gene
. Mutations in the NF1 gene are associated with neurofibromatosis type I
(also known as neurofibromatosis, von Recklinghausen disease, and Watson disease).
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 deficits in learning, 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. 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 regualtes p21ras, PKC and growth response factors.
, mutations in NF1 can also lead to juvenile myelomonocytic leukemia
and Watson syndrome
.
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. This alluded to the same holoenzyme involved in ApoB mRNA editing maybe involved in editing of NF1. 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 GI 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.
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 sufficent for editing to occur by ApoB mRNA editing machinery. This was determined by site mutagenesis experiments.
. 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 with 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 proteins tumour supressor activity. 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 undertaked. 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. 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. The N-terminus of the protein has a region demonstrated to be able to bind microtubule
s. 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 full length neurofiromin protein. This would liberate the full length protein to interact with RAS.
It is thought that RNA editing may account for the wide variation in phenotype of this condition even among siblings. 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.
, with the intitial filing in 1991 and the patent granted in 2001.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the NF1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Mutations in the NF1 gene are associated with neurofibromatosis type I
Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
(also known as neurofibromatosis, von Recklinghausen disease, and Watson disease).
Function
NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the ras signal transduction pathway.NF1 is found within the mammalian postsynapse, where it is known to bind to the NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
complex. It has been found to lead to deficits in learning, and it is suspected that this is a result of its regulation of the Ras pathway. It is known to regulate the GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
HRAS
HRAS
GTPase HRas also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549.- Function :...
, causing the hydrolyzation of GTP and thereby inactivating it. Within the synapse HRAS is known to activate Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
, which itself phosphorylates GRIN2A
GRIN2A
Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene.-Interactions:GRIN2A has been shown to interact with FYN, DLG4, DLG3, DLG1, Src, PTK2B and Interleukin 16.-Further reading:...
, leading to its inclusion in the synaptic membrane.
NF1 is also known to interact with CASK
CASK
Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2 , calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2.-Genomics:This gene is located on the short arm of...
through syndecan
Syndecan
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains, which allow for interaction with a large variety of ligands including...
, a protein which is involved in the KIF17/ABPA1/CASK/LIN7A complex, which is involved in trafficking GRIN2B
GRIN2B
Glutamate [NMDA] receptor subunit epsilon-2 also known as N-methyl D-aspartate receptor subtype 2B is a protein that in humans is encoded by the GRIN2B gene.- Function :...
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 regualtes p21ras, PKC and growth response factors.
Clinical significance
Mutations linked to neurofibromatosis type 1 led to the identification of the NF1 gene. In addition to neurofibromatosis type INeurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
, mutations in NF1 can also lead to juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia is a serious chronic leukemia that affects children mostly aged 4 and younger. The average age of patients at diagnosis is 2 years old. The World Health Organization has included JMML in the category of Myelodysplastic and Myeloproliferative disorders...
and Watson syndrome
Watson syndrome
Watson syndrome is an autosomal recessive condition characterized by Lisch nodules, axillary/inguinal freckling, and neurofibromas.Watson syndrome may be allelic to NF1, the same gene associated with Neurofibromatosis type 1.- References :...
.
Types of Mutations
The neurofibromin gene may be mutated in thousands of ways, resulting in many possible clinical outcomes. Types of mutations include frameshift, nonsense, missense, splicing alteration and deletion mutations, and loss of heterozygosity.Type
The type of editing is a cytidineCytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
to uridine
Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....
(C to U) site specific deamination
Deamination
Deamination is the removal of an amine group from a molecule. Enzymes which catalyse this reaction are called deaminases.In the human body, deamination takes place primarily in the liver, however glutamate is also deaminated in the kidneys. Deamination is the process by which amino acids are...
. The editing site in NF1 mRNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
was determined to have a high homology to the ApoB
Apolipoprotein B
Apolipoprotein B is the primary apolipoprotein of low-density lipoproteins , which is responsible for carrying cholesterol to tissues. While it is unclear exactly what functional role APOB plays in LDL, it is the primary apolipoprotein component and is absolutely required for its formation...
editing site where double stranded mRNA undergoes editing by the ApoB holoenzyme. This alluded to the same holoenzyme involved in ApoB mRNA editing maybe involved in editing of NF1. 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
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
23A. Recent experiments have shown that apobec-1 is indeed expressed outside the GI 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.
Location
The cytidine in the arginineArginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
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 sufficent for editing to occur by ApoB mRNA editing machinery. This was determined by site mutagenesis experiments.
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. 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). Editing occurs in a higher frequency in tumours compared to the relative normal tissues. There is a higher frequency of edting in the NF1 mRNA which includes Exon 23A in tumors.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. 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.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.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 pathwayAnti-apoptotic Ras signalling cascade
The Anti-apoptotic Ras signalling cascade is an intracellular signal transduction cascadethat involves the Ras protein and inhibits apoptosis...
. 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 with 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 proteins tumour supressor activity. 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 undertaked. 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. 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. The N-terminus of the protein has a region demonstrated to be able to bind microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s. 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 full length neurofiromin protein. This would liberate the full length protein to interact with RAS.
Neurofibromitosis
It is thought that RNA editing may account for the wide variation in phenotype of this condition even among siblings. 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.
Patent
The neurofibromatosis gene was patented by the University of MichiganUniversity of Michigan
The University of Michigan is a public research university located in Ann Arbor, Michigan in the United States. It is the state's oldest university and the flagship campus of the University of Michigan...
, with the intitial filing in 1991 and the patent granted in 2001.
External links
- GeneReviews/NCBI/NIH/UW entry on Neurofibromatosis 1
- Human Gene NF1 (uc002hgf.1)
- neurofibromin 1 from GeneCardsGeneCardsGeneCards is a database of human genes that provides genomic, proteomic, transcriptomic, genetic and functional information on all known and predicted human genes. It is being developed and maintained by the Crown Human Genome Center at the Weizmann Institute of Science.- References :*Stelzer G,...
- Database of RNA editing