Alternatively spliced transcript variants encoding different isoforms have also been described for this gene.In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17. It was localized to the long arm of chromosome 17 by chance when researchers discovered chromosome exchanges between chromosome 17 with chromosome 1 and 22. This exchange of genetic material presumably caused a mutation in the neurofibromin gene, leading to the NF1 phenotype. Two recurrent microdeletion types with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion), are found in most cases. Structure
The neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length. However, the protein is 2818 amino acids long leading to the concept of splice variants. For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase activating protein (GAP) family. This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase.Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase, and a second with collapsin response mediator protein.
Furthermore, the heights of children affected by NF-1 have been shown to increase normally until puberty, after which increases in height lessen when compared to healthy counterparts. This eventually causes a shorter stature than expected in individuals with NF-1. Cancer
Cancer can arise in the form of malignant peripheral nerve sheath tumor resulting from malignant degeneration of a plexiform neurofibroma. Frequency. A plexiform neurofibroma has a lifetime risk of 8–12% of transformation into a malignant tumor. Diagnosis. MRI. Treatment. Surgery (primary), radiation therapy. Mortality. Malignant nerve sheath tumor was the main cause of death (60%) in a study of 1895 patients with NF-1 from France in the time period 1980–2006 indicated excess mortality in NF-1 patients compared to the general population. The cause of death was available for 58 (86.6%) patients. The study found excess mortality occurred among patients aged 10 to 40 years. Significant excess mortality was found in both males and females. Cause
Neurofibromin 1 gene
NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin (not to be confused with the disorder itself) which plays a role in cell signaling. The Neurofibromin 1 gene is a negative regulator of the Ras oncogene signal transduction pathway. It stimulates the GTPase activity of Ras. It shows greater affinity for RAS p21 protein activator 1, but lower specific activity. The mRNA for this gene is subject to RNA editing (CGA->UGA->Arg1306Term) resulting in premature translation termination.