NF1 Gene

The NF1 gene (NF1 stands for neurofibromin 1) is a protein-coding gene located on chromosome 17q11.2. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. However, their function has not yet been fully elucidated.

Neurofibromin 1 acts as a negative regulator of the ras signal transduction pathway. NF1 increases the GTPase activity of the active (GTP-bound) Ras form by 1000-fold, resulting in increased production of the inactive GDP-bound Ras form.

Mutations in this gene have been associated with

• Neurofibromatosis Noonan syndrome
• Neurofibromatosis type 1
• Juvenile myelomonocytic leukemia

associated.

The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term), which leads to premature termination of translation. Neurofibromin is produced in many cells, including nerve cells, oligodendrocytes and Schwann cells. It acts as a tumor suppressor. Mutations in the NF1 gene lead to the production of a non-functional version of neurofibromin. A pronounced allelic heterogeneity of the NF1 mutation leads to a variable expressivity of neurofibromin 1.

Neurogenic tumors, e.g. neurofibromas and neurinomas, can form along nerves throughout the body. It is not yet clear which mutations in the NF1 gene lead to the other features of neurofibromatosis type 1, such as café-au-lait spots and intellectual defects.

Mutation detection is extremely complex due to the size of the NF1 gene, the presence of pseudogenes, and the wide variety of mutations (Ko JM et al. 2013). For example, a large Korean NF1 population showed 52 different NF1 mutations identified in 60 families. The mutations included 30 single base substitutions (12 missense and 18 nonsense mutations), 11 missplicing mutations, seven small insertions or deletions, and four large deletions. Sixteen (30.8%) mutations were novel; c.1A>G, c.2033_2034insC, c.2540T>C, c.4537C>T, c.5546G>A, c.6792C>A, and c.6792C>G were consistently identified. The mutations were evenly distributed across exon 1 to intron 47 of NF1. No mutation hotspots were found. Genotype-phenotype analysis suggests that there is no clear relationship between specific mutations and clinical features (Ko JM et al. 2013).

1. Ballester R et al. (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Celet al. l. 63: 851-859.
2. Hattori S et al. (1996) Heterogeneity of GTPase-activating proteins for Ras in the regulation of Ras signal transduction pathway. Yakugaku Zasshi 116: 21-38.
3. Ko JM et al. (2013) Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol 48:447-453.
4. Sabbagh A et al. (2013) NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat 34:1510-1518.