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Wednesday 14 April 2004

Definition: Neurofibromin (NF1) is a member of a family of GTPase-activating proteins, which facilitate conversion of RAS from an active to an inactive state. With loss of NF-1 function, RAS is trapped in an active, signal-emitting state.

The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17qll.2. This gene codes for neurofibromin which is a large 220-250 KDa cytoplasmic protein that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a and 48a).

Function: Neurofibromin, the protein product of the NF1 gene, regulates signal transduction through a RAS protein. Recall that RAS transmits growth-promoting signals and flips back and forth between GDP-binding (inactive) and GTP-binding (active) states.

The functional part of neurofibromin is a GAP, or GTPase-activating protein. GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling.

Loss of RAS control leads to increased activity of other signaling pathways including RAF, ERK1/2, PI3K, PAK and mTOR-S6 kinase.

It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.

Neurofibromin has other growth-regulatory properties besides its ability to regulate RAS activity, but these other functions are poorly understood at this time.

Neurofibromin is 2818 amino acids long with 3 alternatively spiced exons, 9a, 23a, and 48a. The IRA domains are hypothesized to function as negative regulators of RAS, along with the GRD domain in between them.


The neurofibromatosis type 1 gene has one of the highest mutation rates in humans: about 50% of NF1 patients are de novo cases.

Individuals who inherit one mutant allele of the NF-1 gene develop numerous benign neurofibromas as a result of inactivation of the second copy of the gene. This condition is called neurofibromatosis type 1. Some of the neurofibromas later develop into neurofibrosarcomas. Children with neurofibromatosis type 1 also are at increased risk of developing gliomas of the optic nerve.

- germline mutations in neurofibromatosis type 1

  • NF1 microdeletions (40% of somatic mosaicism) (NF1 mosaic deletions) with somatic recombination of the JJAZ1 gene (15257518)

- NF1-associated malformations

  • NF1-associated horseshoe kidney


- Costa RM, Silva AJ. Mouse models of neurofibromatosis type I: bridging the GAP. Trends Mol Med. 2003 Jan;9(1):19-23. PMID: 12524206

- Gutmann DH. The neurofibromatoses: when less is more. Hum Mol Genet. 2001 Apr;10(7):747-55. PMID: 11257108

- Reed N, Gutmann DH. Tumorigenesis in neurofibromatosis: new insights and potential therapies. Trends Mol Med. 2001 Apr;7(4):157-62. PMID: 11286939


- Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglbock H, Maertens O, Messiaen L. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer. 2006 Mar;45(3):265-76. PMID: 16283621

- Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, Evans DG, Howard E, Kerr B, Griffiths S, Consoli C, Side L, Adams D, Pierpont M, Hachen R, Barnicoat A, Li H, Wallace P, Van Biervliet JP, Stevenson D, Viskochil D, Baralle D, Haan E, Riccardi V, Turnpenny P, Lazaro C, Messiaen L. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140-51. PMID: 17160901