Genetics+and+Mechanisms+of+NF1+Gene

Genetics of Neurofibromatosis Type 1:



Gene location and picture from Genetics Home Reference Public Domain.

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The NF1 gene is located on the long (q) arm of [|chromosome 17] at position 11.2. The gene spans approximately 282,750 base pairs. Between base pairs 29,421,944 and 29,704,694. The gene was identified in 1990 by positional cloning, it contains 60 exons with 3 alternative-splice messenger RNAvariants ( Viskochil 2002). =====

How can you develop NF Type 1? Through hereditary mechanisms and Spontaneous mutation in the NF1 gene. NF1 is inherited in an Autosomal Dominant Manner, only one copy of the gene is inherited from the parent.  Figure Obtained from Wikipedia, Public Domain. Licensed under the Creative Commons Attribution-Share Alike 3.0.

Approximately 50% of all NF1 patients have an affected parent and thereby developed the disease due to hereditary mechanisms. While the remaining 50% developed the disease due to a spontaneous mutation in the NF1 gene (Friedman 2012). Most spontaneous mutations occur on the paternal chromosome while most whole gene deletions occur on the maternal chromosome (Friedman 2012). The NF1 mutation rate is among the highest for observed mutation rates in humans with estimates of mutations occurring in 1/7,800 to 1/23,00 gametes (Rasmussen et al 2000). The secondary somatic mutations of the wild type NF1 allele leads to the progression of benign tumors to malignant tumors (Laycock –van spyck et al 2011). As was previously discussed the single mutated copy of the gene alone is not enough to cause disease.

Mechanisms:

The mutations that NF1 generally experiences are inactivating mutations. NF1 encodes for the protein neurofibromin whose main function is the down regulation of Ras signal transduction. When functioning neurofibromin is responsible for the activation of Guanosine Triphosphatase of the Ras proteins which leads to the hydrolysis of bound guanosine triphosphate and the inactivation of the down-stream signal cascade. The mutations that NF1 experiences lead to the inactivation, if not the whole deletion of the protein neurofibromin therefore there is no regulation of Ras, and cell proliferation continues unchecked causing the development of tumors( Viskochil 2002). The Ras signaling pathway is not the only pathway that neurofibromin activates or plays a role in, it is also involved in the MAPk pathway, and the RIG-I-like receptor signaling pathway. Neurofibromin also positively controls Adenylate Cyclase activity and intracellular cAMP levels, which indicates its important role in the Central Nervous system and explains why some patients with Neurofibromatosis Type 1 suffer from cognitive disabilities sometimes to the severity of mental retardation (Gutman et. al 2012).

Neurofibromatosis Type 1