Human pathology

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NF1

neurofibromin

Neurofibromin, the protein product of the NF1 gene, regulates signal transduction through a RAS protein. Recall that RAS transmits growth-promoting signals and flips back and forth between GDP-binding (inactive) and GTP-binding (active) states.

Neurofibromin is a member of a family of GTPase-activating proteins, which facilitate conversion of RAS from an active to an inactive state. With loss of NF-1 function, RAS is trapped in an active, signal-emitting state.

Pathology

The neurofibromatosis type 1 gene has one of the highest mutation rates in humans: about 50% of NF1 patients are de novo cases.

Individuals who inherit one mutant allele of the NF-1 gene develop numerous benign neurofibromas as a result of inactivation of the second copy of the gene. This condition is called neurofibromatosis type 1. Some of the neurofibromas later develop into neurofibrosarcomas. Children with neurofibromatosis type 1 also are at increased risk of developing gliomas of the optic nerve.

- germline mutations in neurofibromatosis type 1

  • NF1 microdeletions (40% of somatic mosaicism) (NF1 mosaic deletions) with somatic recombination of the JJAZ1 gene (15257518)

- NF1-associated malformations

Reviews

- Costa RM, Silva AJ. Mouse models of neurofibromatosis type I: bridging the GAP. Trends Mol Med. 2003 Jan;9(1):19-23. PMID: 12524206

- Gutmann DH. The neurofibromatoses: when less is more. Hum Mol Genet. 2001 Apr;10(7):747-55. PMID: 11257108

- Reed N, Gutmann DH. Tumorigenesis in neurofibromatosis: new insights and potential therapies. Trends Mol Med. 2001 Apr;7(4):157-62. PMID: 11286939

References

- Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglbock H, Maertens O, Messiaen L. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer. 2006 Mar;45(3):265-76. PMID: 16283621

- Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, Evans DG, Howard E, Kerr B, Griffiths S, Consoli C, Side L, Adams D, Pierpont M, Hachen R, Barnicoat A, Li H, Wallace P, Van Biervliet JP, Stevenson D, Viskochil D, Baralle D, Haan E, Riccardi V, Turnpenny P, Lazaro C, Messiaen L. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140-51. PMID: 17160901