PDB rendering based on PDB .
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 von Recklinghausen disease) and Watson syndrome.
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 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 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. In addition to neurofibromatosis type I, mutations in NF1 can also lead to juvenile myelomonocytic leukemia, Watson syndrome, and breast cancer. Types of mutations include frameshift, nonsense, missense, splicing alteration and deletion mutations, and loss of heterozygosity.
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. 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.
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.
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.
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.
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.
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. 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 suppressor 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 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 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.
|Recessive lethal study||Abnormal|
|Glucose tolerance test||Normal|
|Auditory brainstem response||Normal|
|Peripheral blood lymphocytes||Abnormal|
|All tests and analysis from|
Model organisms have been used in the study of NF1 function. A conditional knockout mouse line, called Nf1tm1a(KOMP)Wtsi 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.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and four significant abnormalities were observed. 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.
- Scheffzek, K.; Ahmadian, M. R.; Wiesmüller, L.; Kabsch, W.; Stege, P.; Schmitz, F.; Wittinghofer, A. (1998). "Structural analysis of the GAP-related domain from neurofibromin and its implications". The EMBO Journal 17 (15): 4313–4327. doi:10.1093/emboj/17.15.4313. PMC 1170765. PMID 9687500.
- Skuse GR, Kosciolek BA, Rowley PT (September 1991). "The neurofibroma in von Recklinghausen neurofibromatosis has a unicellular origin". Am. J. Hum. Genet. 49 (3): 600–7. PMC 1683134. PMID 1715669.
- Rasmussen SA, Friedman JM (January 2000). "NF1 gene and neurofibromatosis 1". Am. J. Epidemiol. 151 (1): 33–40. doi:10.1093/oxfordjournals.aje.a010118. PMID 10625171.
- Trovó-Marqui AB, Tajara EH (2006). "Neurofibromin: a general outlook". Clin. Genet. 70 (1): 1–13. doi:10.1111/j.1399-0004.2006.00639.x. PMID 16813595.
- "NF1 mutations and molecular testing", by SA Thomson, L Fishbein and MR Wallace, J Child Neurol 2002 Aug; 17(8); 555-61; discussion 571-2, 646-51
- "Entrez Gene: NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease)".
- The Cancer Genome Atlas Network (2012). "Comprehensive molecular portraits of human breast tumours". Nature (Nature Publishing Group) 490 (7418): 61–70. doi:10.1038/nature11412. PMID 23000897. Retrieved 24 September 2012.
- Bottillo I, Ahlquist T, Brekke H et al. (April 2009). "Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours". J. Pathol. 217 (5): 693–701. doi:10.1002/path.2494. PMID 19142971.
- "Nf1 tumor suppressor in skin:: Expression in response to tissue trauma and in cellular differentiation"
- Eisenbarth, I.; Beyer, K.; Krone, W.; Assum, G. N. (2000). "Toward a Survey of Somatic Mutation of the NF1 Gene in Benign Neurofibromas of Patients with Neurofibromatosis Type 1". The American Journal of Human Genetics 66 (2): 393–401. doi:10.1086/302747. PMC 1288091. PMID 10677298.
- Terzi, Y. K.; Oguzkan, S.; Anlar, B.; Aysun, S.; Ayter, S. (2007). "Neurofibromatosis: Novel and Recurrent Mutations in Turkish Patients". Pediatric Neurology 37 (6): 421–425. doi:10.1016/j.pediatrneurol.2007.07.005. PMID 18021924.
- Skuse GR, Cappione AJ, Sowden M, Metheny LJ, Smith HC (February 1996). "The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing". Nucleic Acids Res. 24 (3): 478–85. doi:10.1093/nar/24.3.478. PMC 145654. PMID 8602361.
- Skuse GR, Ludlow JW (April 1995). "Tumour suppressor genes in disease and therapy". Lancet 345 (8954): 902–6. doi:10.1016/S0140-6736(95)90015-2. PMID 7707816.
- 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". Am. J. Hum. Genet. 70 (1): 38–50. doi:10.1086/337952. PMC 384902. PMID 11727199.
- Backus JW, Smith HC (November 1992). "Three distinct RNA sequence elements are required for efficient apolipoprotein B (apoB) RNA editing in vitro". Nucleic Acids Res. 20 (22): 6007–14. doi:10.1093/nar/20.22.6007. PMC 334467. PMID 1461733.
- Driscoll DM, Zhang Q (August 1994). "Expression and characterization of p27, the catalytic subunit of the apolipoprotein B mRNA editing enzyme". J. Biol. Chem. 269 (31): 19843–7. PMID 8051066.
- Skuse GR, Cappione AJ (1997). "RNA processing and clinical variability in neurofibromatosis type I (NF1)". Hum. Mol. Genet. 6 (10): 1707–12. doi:10.1093/hmg/6.10.1707. PMID 9300663.
- Cappione AJ, French BL, Skuse GR (February 1997). "A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors". Am. J. Hum. Genet. 60 (2): 305–12. PMC 1712412. PMID 9012403.
- Cichowski K, Jacks T (February 2001). "NF1 tumor suppressor gene function: narrowing the GAP". Cell 104 (4): 593–604. doi:10.1016/S0092-8674(01)00245-8. PMID 11239415.
- Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, Buchberg AM, Jenkins NA, Parada LF, Copeland NG (May 1994). "Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues". Genes Dev. 8 (9): 1019–29. doi:10.1101/gad.8.9.1019. PMID 7926784.
- Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F (November 1990). "The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins". Cell 63 (4): 851–9. doi:10.1016/0092-8674(90)90151-4. PMID 2121371.
- Xu GF, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R (August 1990). "The neurofibromatosis type 1 gene encodes a protein related to GAP". Cell 62 (3): 599–608. doi:10.1016/0092-8674(90)90024-9. PMID 2116237.
- Gregory PE, Gutmann DH, Mitchell A, Park S, Boguski M, Jacks T, Wood DL, Jove R, Collins FS (May 1993). "Neurofibromatosis type 1 gene product (neurofibromin) associates with microtubules". Somat. Cell Mol. Genet. 19 (3): 265–74. doi:10.1007/BF01233074. PMID 8332934.
- Huson SM, Compston DA, Clark P, Harper PS (November 1989). "A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity". J. Med. Genet. 26 (11): 704–11. doi:10.1136/jmg.26.11.704. PMC 1015740. PMID 2511318.
- "Dysmorphology data for Nf1". Wellcome Trust Sanger Institute.
- "Peripheral blood lymphocytes data for Nf1". Wellcome Trust Sanger Institute.
- "Salmonella infection data for Nf1". Wellcome Trust Sanger Institute.
- "Citrobacter infection data for Nf1". Wellcome Trust Sanger Institute.
- Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88 (S248): 0. doi:10.1111/j.1755-3768.2010.4142.x.
- Mouse Resources Portal, Wellcome Trust Sanger Institute.
- "International Knockout Mouse Consortium".
- "Mouse Genome Informatics".
- Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- Dolgin E (June 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
- United States Patent US006238861B1
- Upadhyaya M, Shaw DJ, Harper PS (1994). "Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene". Hum. Mutat. 4 (2): 83–101. doi:10.1002/humu.1380040202. PMID 7981724.
- Shen MH, Harper PS, Upadhyaya M (1996). "Molecular genetics of neurofibromatosis type 1 (NF1)". J. Med. Genet. 33 (1): 2–17. doi:10.1136/jmg.33.1.2. PMC 1051805. PMID 8825042.
- Feldkamp MM, Gutmann DH, Guha A (1998). "Neurofibromatosis type 1: piecing the puzzle together". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 25 (3): 181–91. PMID 9706718.
- Hamilton SJ, Friedman JM (2001). "Insights into the pathogenesis of neurofibromatosis 1 vasculopathy". Clin. Genet. 58 (5): 341–4. doi:10.1034/j.1399-0004.2000.580501.x. PMID 11140831.
- Baralle D, Baralle M (2006). "Splicing in action: assessing disease causing sequence changes". J. Med. Genet. 42 (10): 737–48. doi:10.1136/jmg.2004.029538. PMC 1735933. PMID 16199547.
- Mensink KA, Ketterling RP, Flynn HC et al. (2006). "Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature". J. Med. Genet. 43 (2): e8. doi:10.1136/jmg.2005.034256. PMC 2603036. PMID 16467218.
- Trovó-Marqui AB, Tajara EH (2006). "Neurofibromin: a general outlook". Clin. Genet. 70 (1): 1–13. doi:10.1111/j.1399-0004.2006.00639.x. PMID 16813595.
- GeneReviews/NCBI/NIH/UW entry on Neurofibromatosis 1
- Human Gene NF1 (uc002hgf.1)
- neurofibromin 1 from GeneCards
- Database of RNA editing