NF1

Official Full Name

neurofibromin 1

Organism

Homo sapiens

GeneID

4763

Background

This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

Synonyms

WSS; NFNS; VRNF;

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Detailed Information

Neurofibromatosis type 1, also known as von Recklinghausen's disease or NF1, is a tumour predisposition syndrome characterized by the development of multiple neurofibromas, Lisch nodules and café-au-lait spots. The NF1 gene is a typical tumour suppressor gene on chromosome 17. NF1 is caused by heterozygous germline mutations in the tumor suppressor gene NF1 that codes for neurofibromin, a negative regulator of the RAS proto-oncogene. To date, more than a thousand different NF1 germline mutations ranging from intragenic point mutations to large deletions encompassing the entire NF1 gene and flanking genes (NF1 micro-deletions) have been described. Individuals with NF1 have an increased risk of developing various tumours, including leukaemia, glioma, malignant peripheral nerve sheath tumour (MPNST), phaeochromocytoma, rhabdomyosarcoma and breast cancer.

NF1 and neurofibromin in tumour suppression

NF1 is considered as a classical tumour suppressor gene, with both copies of the NF1 gene reported to be inactivated in both benign and malignant tumours in NF1 patients. Various Nf1+/− mouse models show predisposition to tumour formation, including MPNST, phaeochromocytomas, and leukaemias, similar to the spectrum of NF1-associated malignancies observed in human counterparts. The tumour suppressor function of neurofibromin is mainly attributed to a small central region which comprises 360 amino acids encoded by exons 20-27a. This critical region has significant structural and sequence similarity to ras-guanosine-triphosphate (GTP)ase activation proteins (GAPs), which is known as the GAP-related domain (GRD). GAPs inactivate Ras by accelerating the conversion of active Ras-GTP to inactive guanosine diphosphate (GDP)-bound form. The downregulation of oncogene Ras by neurofibromin inhibits the downstream activation of mitogen-activated protein kinase (MAPK) and the PI3K/Akt/mTOR cell proliferation and differentiation pathways. Besides, neurofibromin 1 is involved in cAMP signaling.

NF1 Figure 1. The RAS/MAPK pathway and RASopathies. (Kiuru M, Busam K J., 2017)

NF1 and tumour

Tumors originating from terminal sensory nerve branches of the skin are called dermal or cutaneous neurofibromas. They are usually small but numerous, rarely develop before puberty and do not develop into malignancy. Almost all NF1 patients develop at least a few of these tumors in their lifetime. In contrast, plexiform neurofibromas affect only one third of NF1 patients and are thought to be present at birth. They are associated with major nerve trunks or plexi, may present as a large, disfiguring mass, and can progress to malignancy with an estimated lifetime risk of 8-13%. Epidemiological studies suggest that the overall risk for brain tumors is five times higher in NF1 patients than in the general population. The vast majority of these tumors are WHO grade I pilocytic astrocytomas, located in any part of the optic nerves, chiasm and optic tracts. Niemeyer et al. demonstrated that NF1 children have a 350-fold increased risk to develop juvenile myelomonocytic leukemia (JMML), a rare mixed myelodysplastic/myeloproliferative disorder that accounts for only 2% of all pediatric hematopoietic malignancies in the general population. Many other tumor entities have been reported to occur with increased frequency in NF1. A recent population-based study has shown that the range of NF1-associated tumors extends far beyond nervous system or neural crest-derived tumors and includes cancers of the lung, skin, ovary, thyroid gland and gastrointestinal tract as well as several hematological malignancies. Notably, women with NF1 have an up to 3 fold increased risk to develop breast cancer.

Therapeutic Strategies for NF1-associated Tumours

Since the major consequence of NF1 mutation is the increased RAS/MAPK pathway signaling, therapeutic targeting of this pathway for NF1 and NF1-associated/deficient malignancies is reasonable and supported by preclinical evidence. Moreover, inhibitors of the PI3K/mTOR and cAMP pathways have shown promise for targeting NF1-deficient tumors. The downstream effects of NF1 deficiency may be dependent on the cell type, and should be kept in mind in the development of targeted therapies. Preclinical and clinical trials for the treatment of NF1-associated tumors, MPNSTs, neurofibromas, and plexiform neurofibromas, include tyrosine kinase inhibitors, mTOR inhibitors, and MEK inhibitors. Inhibition of MEK led to significant reduction of neurofibroma volume in Nf1 mutant mice and in prolonged survival of mice with human MPNST xenografts. Interestingly, MEK inhibition also improves hematology and prolonged survival in a Nf1 mouse model of JMML. The rapidly increasing understanding of the role of NF1 mutations in neoplasia and neurofibromin 1 in various cellular signaling pathways will likely produce novel treatment methods relevant for individuals with NF1 and for sporadic tumors with NF1 mutations.

References:

Wegscheid M L, et al. Human stem cell modeling in neurofibromatosis type 1 (NF1). Experimental neurology, 2018, 299: 270-280.
Rosenbaum T, Wimmer K. Neurofibromatosis type 1 (NF1) and associated tumors. Klinische Pädiatrie, 2014, 226(06/07): 309-315.
Yap Y S, et al. The NF1 gene revisited–from bench to bedside. Oncotarget, 2014, 5(15): 5873.
Kiuru M, Busam K J. The NF1 gene in tumor syndromes and melanoma. Laboratory investigation, 2017, 97(2): 146-157.
Philpott C, et al. The NF1 somatic mutational landscape in sporadic human cancers. Human genomics, 2017, 11(1): 1-19.

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