Neurofibromatosis Type I (NF1)

Abstract

Neurofibromatosis type I (NF1) is a common, autosomal dominant condition that manifests as multiple café‐au‐lait spots, peripheral nerve sheath tumours, optic nerve pathway tumours, orthopaedic abnormalities and learning disabilities. The gene for NF1 encodes neurofibromin, a RasGTPase activating protein (RasGAP) that activates the intrinsic GTPase of Ras and negatively regulates its role in signal transduction. As a tumour suppressor, inactivating mutations in NF1 lead to increased intracellular Ras signalling. Other components of the Ras‐MAP(mitogen‐activated protein) kinase pathway are now known to be involved in other genetic conditions including Noonan syndrome, Costello syndrome, Cardio‐facial‐cutaneous syndrome and Legius syndrome. NF1 is a neurocutaneous disorder that is a paradigm for many principles in the practice of medical genetics: variable clinical expressivity, penetrance, pleiotropy, age‐dependent clinical expression and mosaicism. The development of inhibitors of the Ras‐MAPK pathway, and other Ras‐connected pathways, opens new avenues of therapeutic intervention for myriad complications of this disorder.

Key concepts

  • Tumour suppressor: The NF1 gene loosely fits the paradigm of the “two‐hit” model of tumour suppressor in that somatic inactivation of a haploinsufficient gene in a subset of cells leads to tumour development.

  • Variability of clinical expressivity: NF1 demonstrates multiple phenotypes, even in the same family where all affected individuals have the identical gene mutation.

  • Age‐related penetrance: The clinical manifestations of NF1 arise at different ages and the condition is fully penetrant in adults.

  • Genomic structure: The NF1 gene is traditional in its gene structure, yet there are unique features including embedded genes transcribed in the opposite orientation and multiple disease‐causing translocation breakpoints.

  • Value of diagnostic criteria: NF1 is one of the few genetic conditions that can be diagnosed by the application of seven diagnostic criteria.

  • Mosaicism: NF1 has a high sporadic incidence, and somatic mutations occurring in early pregnancy can lead to a mosaic clinical presentation evident by skin manifestations.

  • Positional cloning: The NF1 gene was identified by application of genetic and physical mapping techniques.

  • Animal models: Animal models, particularly the conditional mice, have been instrumental in furthering our understanding of this condition.

  • Integration of kinase pathways: The Ras‐MAPK pathway is integrated in the intracellular network of signalling that includes growth factor receptors at the cell membrane.

  • Pathophysiology: The understanding of the biochemical pathway and processes leading to tumour formation have led to the design and application of specific therapeutics that would not otherwise have been considered in the treatment of NF1.

Keywords: café‐au‐lait spots; neurofibroma; autosomal dominant; variable expressivity; Ras signal transduction

Figure 1.

Neurofibromin‐Ras signal transduction pathway. Neurofibromin stimulates the hydrolysis of GTP‐bound Ras to GDP‐bound ras. If neurofibromin does not interact with Ras, a strong Ras‐GTP signal is sent to the nucleus (arrows on the left), whereas the presence of neurofibromin inactivates Ras‐GTP, which results in diminution of signal transduction, as shown by the arrows on the right. GDP, guanosine diphosphate; GTP, guanosine triphosphate; MAPK, mitogen‐activated protein kinase; Pi, inorganic phosphate.

Figure 2.

The NF1 (neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease)) gene locus on the long arm of chromosome 17. The primary transcript is denoted above the genomic block and it spans approximately 350 kb. There are two translocation breakpoints that helped to physically map this locus. Cent, centromere; Tel, telomere.

Figure 3.

NF1 exons are displayed by green rectangles with the alternative splice variants 9a, 23a and 48a displayed in blue. The catalytic Ras‐GTPase activating domain (GAP‐related domain, GRD) is displayed as yellow rectangles. Three genes are embedded in NF1 intron 35: OMG(oligodendrocyte myelin glycoprotein), EVI2B (ecotropic viral integration site 2B) and EVI2A (ecotropic viral integration site 2A). All two‐exon genes are transcribed from the complementary strand of NF1. Alu and (CA)n are informative polymorphic sites.

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Further Reading

Gutmann DH, Aylsworth A, Carey J et al. (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Journal of the American Medical Association 278: 51–57.

Huson SM and Hughes RAC (1994) The Neurofibromatoses: A Pathogenetic and Clinical Overview. London, UK: Chapman & Hall Medical.

Rubenstein AE and Korf BR (eds) (1990) Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. New York, NY: Thieme Medical Publishers.

Upadhyaya M and Cooper DN (1998) Neurofibromatosis Type 1: From Genotype to Phenotype. Oxford, UK: BIOS Scientific Publishers Limited.

Web Links

NF1 (Neurofibromin 1 (Neurofibromatosis, von Recklinghausen Disease, Watson Disease)); LocusID: 4763. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4763

NF1 (Neurofibromin 1 (Neurofibromatosis, von Recklinghausen Disease, Watson Disease)); MIM number: 162200. OMIM: http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?162200

OMG (Oligodendrocyte Myelin Glycoprotein); LocusID: 4974. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4974

OMG (Oligodendrocyte Myelin Glycoprotein); MIM number: 164345. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?164345.

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How to Cite close
Viskochil, David(Sep 2009) Neurofibromatosis Type I (NF1). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005534.pub2]