[6][7][8] Neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP.

[6][7] Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

[19] OMG is a membrane glycoprotein that is expressed in the human central nervous system during myelination of nerve cells.

[20] Although no core promoter element has been found, consensus binding sequences have been identified in the 5' UTR for several transcription factors such as Sp1 and AP2.

This map showed that three of the regions (at approximately – 1000, – 3000, and – 4000) were frequently methylated, but the cytosines near the transcription start site were unmethylated.

[18] It was verified that there are two NF1 polyadenylated transcripts that differ in size because of the length of the 3' UTR, which is consistent with what has been found in the mouse gene.

[18] A study conducted in 2000 examined whether the involvement of the 3' UTR in post-transcriptional gene regulation had an effect on the variation of NF1 transcript quantity both spatially and temporally.

[22] HuR binds to AU-rich elements which are scattered throughout the 3' UTR and are thought to be negative regulators of transcript stability.

[6][7][8] Neurofibromin is a GTPase-activating protein (GAP) that negatively regulates Ras pathway activity by accelerating hydrolysis of Ras-bound guanosine triphosphate (GTP).

[8][9] The catalytic RasGAP activity of neurofibromin is located in a central portion of the protein, that is called the GAP-related domain (GRD).

[9] The Ras-binding region is found in the surface of GAPc and consists of a shallow pocket that is lined by conserved amino acid residues.

[9] Sec14 domains are defined by a lipid binding pocket that resembles a cage and is covered by a helical lid portion that is believed to regulate ligand access.

[9] The PH-like region displays a protrusion that connects two beta-strands from the PH core that extend to interact with the helical lid found in the Sec14 domain.

[27] If the edited transcript is translated, it produces a protein that cannot function as a tumor suppressor because the N-terminal of the GRD is truncated.

[30][31] Café-au-lait spots are the most common sign of NF1, but other symptoms include lisch nodules of iris, cutaneous neurofibromas (CNF), plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), attention deficits, learning deficits and other cognitive disabilities.

[6][7][10] In addition to neurofibromatosis type I, mutations in NF1 can also lead to juvenile myelomonocytic leukemias (JMML), gastrointestinal stromal tumors (GIST), Watson syndrome, astrocytic neoplasms, phaeochromocytomas and breast cancer.

[6][32] However, in April, 2020,[33] the FDA approved selumetinib (brand name Koselugo) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).

[6]) Research based on these preclinical models has already proven its efficacy as multiple clinical assays have been initiated subsequently regarding neurofibromatosis type 1-related plexiform neurofibromas, gliomas, MPNST and neurocognitive disorders.

In 2013, two conditional knockout mouse models, called Dhh-Cre;Nf1flox/flox[45] (which develops neurofibromas similar to those found in NF1 patients) and Mx1-Cre;Nf1flox/flox[46] (which develops myeloproliferative neoplasms similar to those found in NF1 juvenile myelomonocytic leukemia/JMML) were used to study the effects of the specific MEK inhibitor PD032590 on tumor progression.

[48] These unprecedented and promising results from the phase II SPRINT trial,[48][49] led, first in 2018, both the Food and Drug Administration (FDA) and the European Medicines Agency to grant selumetinib an Orphan Drug Status for the treatment of neurofibromatosis type 1, and then, a few months later in 2019, FDA to grant a Breakthrough Therapy Designation to the inhibitor.

[53] It comprises an IRA-related central segment containing the catalytic GAP-related domain (GRD), which are both highly similar to their human counterparts.

[35][53] dNF1, like its human counterpart, is mainly expressed in the developing and adult nervous system[54][55] and primarily controls the MAPK RAS/ERK signaling pathway.

[62][63][64][55] Large scale genetic and functional screens have also led to the identification of dominant modifier genes responsible for the dNF1-associated defects.