Neurofibromatosis Type I (NF1)


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.



Aoki Y, Niihori T, Kawame H et al. (2005) Germline mutations in HRAS proto‐oncogene cause Costello syndrome. Nature Genetics 37: 1038–1040.

Bernards A (1995) Neurofibromatosis type I and Ras‐mediated signaling: filling in the GAPs. Biochimica et Biophysica Acta 1242: 43–59.

Bernards A and McClatchey A (2001) Neurofibromatoses. In: Fisher DE (ed.) Tumor Suppressor Genes in Human Cancer, pp. 253–280. Totowa, NJ: Humana Press, Inc.

Bollag G, Clapp DW, Shih S et al. (1996) Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nature Genetics 12: 144–148.

Brannan C, Perkins A, Vogel K et al. (1994) Targeted disruption of the neurofibromatosis type‐1 gene leads to developmental abnormalities in heart and various neural crest‐derived tissues. Genes & Development 8: 1019–1029.

Brems H, Chmara M, Sahbatou M et al. (2007) Germline loss‐of‐function mutations in SPRED1 cause a neurofibromatosis 1‐like phenotype. Nature Genetics 39: 1120–1126.

Carey J and Viskochil D (1999) Neurofibromatosis type I: a model condition for the study of the molecular basis of variable expressivity in human disorders. American Journal of Medical Genetics 89: 7–13.

Carroll SL and Ratner N (2008) How does the Schwann cell lineage form tumors in NF1? Glia 56: 1590–1605.

Cichowski K, Shih T, Schmitt E et al. (1999) Mouse models of tumor development in neurofibromatosis type 1. Science 286: 2172–2176.

Costa RM, Federov NB, Kogan JH et al. (2002) Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415: 526–530.

Cui Y, Costa RM, Murphy GG et al. (2008) Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135: 549–560.

Easton DF, Ponder MA, Huson SM and Ponder BA (1993) An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. American Journal of Human Genetics 53: 305–313.

Eerola I, Boon LM, Mulliken JB et al. (2003) Capillary malformation‐arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. American Journal of Human Genetics 73: 1240–1249.

Elefteriou F, Benson MD, Sowa H et al. (2006) ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metabolism 4: 441–451.

Fahsold R, Hoffmeyer S, Mischung C et al. (2000) Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP‐related domain. American Journal of Human Genetics 66: 790–818.

Friedman JM, Gutmann DH, MacCollin M and Riccardi VM (1999) Neurofibromatosis: Phenotype, Natural History, and Pathogenesis, 3rd edn. Baltimore, MD: The Johns Hopkins University Press.

Guha A, Lau N, Huvar I et al. (1996) Ras‐GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene 12: 507–513.

Hawes JJ, Tuskan RG and Reilly KM (2007) Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies. Neurogenetics 8: 121–130.

Jacks T, Shih TS, Schmitt EM et al. (1994) Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nature Genetics 17: 353–361.

Kolanczyk M, Kossler N, Kühnisch J et al. (2007) Multiple roles for neurofibromin in skeletal development and growth. Human Molecular Genetics 16: 874–886.

Krab L, de Goede‐Bolder A, Aarsen F et al. (2008) Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. Journal of the American Medical Association 300: 287–294.

Largaespada D, Brannan C, Jenkins N and Copeland N (1996) Nf1 deficiency causes Ras‐mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia. Nature Genetics 12: 137–143.

Lasater EA, Bessler WK, Mead LE et al. (2008) Nf1+/− mice have increased neointima formation via hyperactivation of a Gleevec sensitive molecular pathway. Human Molecular Genetics 17: 2336–2344.

Le L and Parada L (2007) Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene 26: 4609–4616.

Le L, Shipman T, Burns D and Parada L (2009) Cell of origin and microenvironment contribution for NF1‐associated dermal neurofibromas. Cell Stem Cell 4: 453–463.

Li Y, O'Connell P, Huntsman‐Breidenbach H et al. (1995) Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 25: 9–18.

Messiaen LM, Callens T, Mortier G et al. (2000) Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Human Mutation 15: 541–555.

National Institute of Health Consensus Development Conference (1988) Neurofibromatosis: conference statement. Archives of Neurology 45: 575–578.

Niihori T, Aoki Y, Narumi Y et al. (2006) Germline KRAS and BRAF mutations in cardio‐facio‐cutaneous syndrome. Nature Genetics 38: 294–296.

Regnier V, Meddeb M, Lecointre G et al. (1997) Emergence and scattering of multiple neurofibromatosis (NF1)‐related sequences during hominoid evolution suggest a process of pericentromeric interchromosomal transposition. Human Molecular Genetics 6: 9–16.

Reilly KM and Van Dyke T (2008) It takes a (dysfunctional) village to raise a tumor. Cell 135: 408–410.

Rodriguez‐Viciana P, Tetsu O, Tidyman WE et al. (2006) Germline mutations in genes within the MAPK pathway cause cardio‐facio‐cutaneous syndrome. Science 311: 1287–1290.

Schubbert S, Zenker M, Rowe SL et al. (2006) Germline KRAS mutations cause Noonan syndrome. Nature Genetics 38: 331–336.

Serra E, Rosenbaum T, Winner U et al. (2000) Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Human Molecular Genetics 9: 3055–3064.

Side L, Taylor B, Cayoutte M et al. (1997) Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type I and malignant myeloid disorders. New England Journal of Medicine 336: 1713–1720.

Silva AJ, Frankland PW, Marowitz Z et al. (1997) A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nature Genetics 15: 281–284.

Stevenson DA, Zhou H, Ashrafi S et al. (2006) Double inactivation of NF1 in tibial pseudarthrosis. American Journal of Human Genetics 79: 143–148.

Swensen J and Viskochil D (2008) The Ras pathway. In: Epstein C (ed.) Inborn Errors of Development, 2nd edn. New York: Oxford University Press Inc.

Tartaglia M, Mehler EL, Goldberg R et al. (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP‐2, cause Noonan syndrome. Nature Genetics 29: 465–468.

Upadhyaya M, Huson S, Davies M et al. (2007) 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. American Journal of Human Genetics 80: 140–151.

Viskochil DH, Buchberg AM, Xu G et al. (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type I locus. Cell 62: 187–192.

Viskochil D, White R and Cawthon R (1993) The neurofibromatosis type I gene. Annual Review of Neuroscience 16: 183–205.

Vogel K, Brannan C, Jenkins N, Copeland N and Parada L (1995) Loss of neurofibromin results in neurotrophin‐independent survival of embryonic sensory and sympathetic neurons. Cell 82: 733–742.

Vogel K, Klesse L, Velasco‐Miguel S et al. (1999) Mouse tumor model for neurofibromatosis type 1. Science 286: 2176–2179.

Yang FC, Chen S, Robling AG et al. (2006) Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1‐haploinsufficient osteoclast functions. The Journal of Clinical Investigation 116: 2880–2891.

Yang FC, Ingram DA, Chen S et al. (2003) Neurofibromin‐deficient Schwann cells secrete a potent migratory stimulus for Nf1+/− mast cells. The Journal of Clinical Investigation 112: 1851–1861.

Yang FC, Ingram D, Chen S et al. (2008) Nf1‐dependent tumors require a microenvironment containing Nf1+/‐‐ and c‐kit‐dependent bone marrow. Cell 135: 437–448.

Zhu Y, Ghosh P, Charnay P, Burns DK and Parada LF (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296: 920–922.

Zhu Y, Romero M, Ghosh P et al. (2001) Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes & Development 15: 859–876.

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:

NF1 (Neurofibromin 1 (Neurofibromatosis, von Recklinghausen Disease, Watson Disease)); MIM number: 162200. OMIM:‐post/Omim/dispmim?162200

OMG (Oligodendrocyte Myelin Glycoprotein); LocusID: 4974. LocusLink:

OMG (Oligodendrocyte Myelin Glycoprotein); MIM number: 164345. OMIM:‐post/Omim/dispmim?164345.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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