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 horseshoe kidney
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