NF1 was
cloned in 1990 and its product neurofibromin was identified in 1992. Neurofibromin, a
GTPase-activating protein, primarily regulates the protein
Ras.
NF1 is located on the long arm of
chromosome 17, position q11.2 58 of these exons are constitutive and 4 exhibit
alternative splicing ( 9a, 10a-2, 23a, and 28a). There are three genes that are present within
intron 27b of
NF1. These genes are
EVI2B,
EVI2A and
OMG, which are encoded on the opposite strand and are transcribed in the opposite direction of
NF1. OMG is a
membrane glycoprotein that is expressed in the human
central nervous system during
myelination of
nerve cells. The
open reading frame is 8,520-bp long and begins at the translation initiation site. It has been shown that the CREB site must be intact for normal promoter activity to occur and methylation at the Sp1 sites may affect promoter activity. HuR binds to
AU-rich elements which are scattered throughout the 3' UTR and are thought to be negative regulators of transcript stability. however mutation detection is difficult because of its large size, the presence of
pseudogenes, and the variety of possible mutations. The
NF1 locus has a high incidence of
de novo mutations, meaning that the mutations are not inherited maternally or paternally
. Although the mutation rate is high, there are no mutation "hot spot" regions. Mutations tend to be distributed within the gene, although exons 3, 5, and 27 are common sites for mutations. The Human Gene Mutation Database contains 1,347
NF1 mutations, but none are in the "regulatory" category. There have not been any mutations conclusively identified within the promoter or untranslated regions. This may be because such mutations are rare, or they do not result in a recognizable
phenotype. There have been mutations identified that affect
splicing, in fact 286 of the known mutations are identified as splicing mutations. About 78% of splicing mutations directly affect
splice sites, which can cause aberrant splicing to occur. Aberrant splicing may also occur due to mutations within a
splicing regulatory element.
Intronic mutations that fall outside of splice sites also fall under splicing mutations, and approximately 5% of splicing mutations are of this nature.
Point mutations that effect splicing are commonly seen and these are often substitutions in the regulatory sequence. Exonic mutations can lead to deletion of an entire exon, or a fragment of an exon if the mutation creates a new splice site. Intronic mutations can result in the insertion of a cryptic exon, or result in
exon skipping if the mutation is in the conserved 3' or 5' end. == Protein ==