neurofibromatosis 1 genes


Summary: Tumor suppressor genes located on the long arm of human chromosome 17 in the region 17q11.2. Mutation of these genes is thought to cause NEUROFIBROMATOSIS 1, Watson syndrome, and LEOPARD syndrome.

Top Publications

  1. Castle B, Baser M, Huson S, Cooper D, Upadhyaya M. Evaluation of genotype-phenotype correlations in neurofibromatosis type 1. J Med Genet. 2003;40:e109 pubmed
  2. Ars E, Kruyer H, Morell M, Pros E, Serra E, Ravella A, et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003;40:e82 pubmed
  3. De Luca A, Buccino A, Gianni D, Mangino M, Giustini S, Richetta A, et al. NF1 gene analysis based on DHPLC. Hum Mutat. 2003;21:171-2 pubmed
    ..None of the missense mutations identified in this study were found after screening of 150 controls. Our results suggest that DHPLC provides an accurate method for the rapid identification of NF1 mutations. ..
  4. Vandenbroucke I, Vandesompele J, De Paepe A, Messiaen L. Quantification of NF1 transcripts reveals novel highly expressed splice variants. FEBS Lett. 2002;522:71-6 pubmed
    ..NF1-DeltaE43 lacks a nuclear targeting sequence and might be functionally different from full-length NF1. These novel NF1 splice variants might expand our understanding of the role of neurofibromin. ..
  5. Brannan C, Perkins A, Vogel K, Ratner N, Nordlund M, Reid S, et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 1994;8:1019-29 pubmed
    ..These results identify new roles for NF1 in development and indicate that some of the abnormal growth phenomena observed in NF1 patients can be recapitulated in neurofibromin-deficient mice. ..
  6. Vandenbroucke I, Vandesompele J, Paepe A, Messiaen L. Quantification of splice variants using real-time PCR. Nucleic Acids Res. 2001;29:E68-8 pubmed
    ..In addition, we validate the use of an absolute standard curve based on a dilution series of fluorometrically quantified PCR products. ..
  7. Messiaen L, Callens T, Mortier G, Beysen D, Vandenbroucke I, van Roy N, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15:541-55 pubmed
    ..We found a high frequency of unusual splice mutations outside of the AG/GT 5 cent and 3 cent splice sites. As some of these mutations form stable transcripts, it remains possible that a truncated neurofibromin is formed. ..
  8. Park V, Kenwright K, Sturtevant D, Pivnick E. Alternative splicing of exons 29 and 30 in the neurofibromatosis type 1 gene. Hum Genet. 1998;103:382-5 pubmed
    ..RNA from mice revealed only constitutive expression in this region of the NF1 gene. This study adds a new site of alternative processing to the complex expression of NF1. ..
  9. Suzuki Y, Suzuki H, Kayama T, Yoshimoto T, Shibahara S. Brain tumors predominantly express the neurofibromatosis type 1 gene transcripts containing the 63 base insert in the region coding for GTPase activating protein-related domain. Biochem Biophys Res Commun. 1991;181:955-61 pubmed
    ..We suggest that higher levels of type II mRNA may be related to the genesis of brain tumors. ..

More Information


  1. Inagaki H, Ohye T, Kogo H, Yamada K, Kowa H, Shaikh T, et al. Palindromic AT-rich repeat in the NF1 gene is hypervariable in humans and evolutionarily conserved in primates. Hum Mutat. 2005;26:332-42 pubmed
    ..Although such palindromic regions are usually unstable and disappear rapidly due to deletion, the 17PATRR in the NF1 gene was stably conserved during evolution for reasons that are still unknown. ..
  2. Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kücükceylan N, et al. 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. Am J Hum Genet. 2000;66:790-818 pubmed
    ..Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggest significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16. ..
  3. Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman J, Fryns J. Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat. 1996;8:51-6 pubmed
    ..We hypothesize that some patients now diagnosed with LEOPARD syndrome have in fact a mutation in the NF1 gene, whereas in other patients with LEOPARD syndrome, a different gene might be involved. ..
  4. Largaespada D, Brannan C, Jenkins N, Copeland N. Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia. Nat Genet. 1996;12:137-43 pubmed
    ..Finally, we describe a genetic screen for identifying genes that cooperate with Nf1 gene loss during progression to acute myeloid leukaemia. ..
  5. Andersen L, Ballester R, Marchuk D, Chang E, Gutmann D, Saulino A, et al. A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity. Mol Cell Biol. 1993;13:487-95 pubmed
    ..The strong conservation of this alternative splicing suggests that both type I and II isoforms mediate important biological functions of neurofibromin. ..
  6. Jacks T, Shih T, Schmitt E, Bronson R, Bernards A, Weinberg R. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994;7:353-61 pubmed
    ..The wild-type Nf1 allele is lost in approximately half of the tumours from heterozygous animals. In addition, homozygosity for the Nf1 mutation leads to abnormal cardiac development and mid-gestational embryonic lethality. ..
  7. Marchuk D, Saulino A, Tavakkol R, Swaroop M, Wallace M, Andersen L, et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics. 1991;11:931-40 pubmed
    ..The gene extends for approximately 300 kb on chromosome 17, with its promoter in a CpG-rich island. ..
  8. Messiaen L, Callens T, De Paepe A, Craen M, Mortier G. Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene. Hum Genet. 1997;101:75-80 pubmed
    ..This is the first report showing that nonsense mutations in the NF1 gene can induce the skipping of a constitutive exon. ..
  9. Danglot G, Regnier V, Fauvet D, Vassal G, Kujas M, Bernheim A. Neurofibromatosis 1 (NF1) mRNAs expressed in the central nervous system are differentially spliced in the 5' part of the gene. Hum Mol Genet. 1995;4:915-20 pubmed
    ..The results presented here are consistent with tissue-specific expression of this alternative exon which we propose to call exon 9br. ..
  10. Lazaro C, Gaona A, Ainsworth P, Tenconi R, Vidaud D, Kruyer H, et al. Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum Genet. 1996;98:696-9 pubmed
    ..05). Our results suggest that in NF1 the majority of deletions occur in oogenesis, while other types of mutations should account for the paternally derived NF1 mutations. ..
  11. Oguzkan S, Terzi Y, Guler E, Derbent M, Agras P, Saatci U, et al. Two neurofibromatosis type 1 cases associated with rhabdomyosarcoma of bladder, one with a large deletion in the NF1 gene. Cancer Genet Cytogenet. 2006;164:159-63 pubmed
    ..1, IVS27EVI-20, IVS27AC24.8, IVS27AC28.4, M98509, IVS27AC33.1, IVS38TG53.0) and one extragenic polymorphic marker (3'NF1). A large deletion was detected in the NF1 gene in the NF1-Noonan syndrome (NF-NS) case associated with RMS. ..
  12. Li Y, O Connell P, Breidenbach H, Cawthon R, Stevens J, Xu G, et al. Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics. 1995;25:9-18 pubmed
    ..This information should be useful for implementing a comprehensive NF1 mutation screen using genomic DNA as template. ..
  13. Bendova S, Krepelova A, Petrak B, Kinstova L, Musova Z, Rausova E, et al. Novel mutations in the NF1 gene in Czech patients with neurofibromatosis type 1. J Mol Neurosci. 2007;31:273-9 pubmed
    ..2329 T>G, c.2816delA, c.3738_3741delGTTT, c.4733 C>T, c.5220delT, c.6473_6474insGAAG, ex14_49del, ex28_49del. We present this study as a first effectual step in the routine diagnosis of the NF1 in patients from the Czech Republic. ..
  14. Costa R, Yang T, Huynh D, Pulst S, Viskochil D, Silva A, et al. Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nat Genet. 2001;27:399-405 pubmed
    ..Our findings have implications for the development of a treatment for the learning disabilities associated with NF1 and indicate that the GAP domain of NF1 modulates learning and memory. ..
  15. Kehrer Sawatzki H, Cooper D. Mosaicism in sporadic neurofibromatosis type 1: variations on a theme common to other hereditary cancer syndromes?. J Med Genet. 2008;45:622-31 pubmed publisher
  16. Chao R, Pyzel U, Fridlyand J, Kuo Y, Teel L, Haaga J, et al. Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell. 2005;8:337-48 pubmed
    ..Nf1(+/-) mice provide a tractable model for investigating the pathogenesis of common mutagen-induced cancers and for testing preventive strategies. ..
  17. Gutzmer R, Herbst R, Mommert S, Kiehl P, Matiaske F, Rutten A, et al. Allelic loss at the neurofibromatosis type 1 (NF1) gene locus is frequent in desmoplastic neurotropic melanoma. Hum Genet. 2000;107:357-61 pubmed
    ..DNM may represent an interesting tumour model tor the further elucidation of the cellular functions and tumour-suppressive potential of neurofibromin. ..
  18. Nyström A, Ekvall S, Stromberg B, Holmstrom G, Thuresson A, Anneren G, et al. A severe form of Noonan syndrome and autosomal dominant café-au-lait spots - evidence for different genetic origins. Acta Paediatr. 2009;98:693-8 pubmed publisher
  19. Xu G, O Connell P, Stevens J, White R. Characterization of human adenylate kinase 3 (AK3) cDNA and mapping of the AK3 pseudogene to an intron of the NF1 gene. Genomics. 1992;13:537-42 pubmed
  20. Barkan B, Starinsky S, Friedman E, Stein R, Kloog Y. The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1. Clin Cancer Res. 2006;12:5533-42 pubmed
    ..FTS treatment of NF1 cells normalized Ras-GTP levels, resulting in reversal of the transformed phenotype and inhibition of tumor growth. FTS may therefore be considered as a potential drug for the treatment of NF1. ..
  21. Ohno K. [The results of recent research in neurocutaneous syndromes]. No To Hattatsu. 1998;30:109-14 pubmed
    ..In addition, in the Eker rat with hereditary renal carcinoma, a mutation in the TSC2 gene has been identified. In this review I mentioned briefly several issues to be clarified in the near future. ..
  22. Altarescu G, Brooks B, Kaplan Y, Eldar Geva T, Margalioth E, Levy Lahad E, et al. Single-sperm analysis for haplotype construction of de-novo paternal mutations: application to PGD for neurofibromatosis type 1. Hum Reprod. 2006;21:2047-51 pubmed
    ..This method is generally applicable to PGD for any disease in which the haplotype of paternal mutations cannot be determined by typing relatives. ..
  23. Repunte Canonigo V, van der Stap L, Chen J, Sabino V, Wagner U, Zorrilla E, et al. Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake. Brain Res. 2010;1339:1-10 pubmed publisher
    ..Altogether, the data implicate K-ras-regulated pathways in the regulation of excessive alcohol drinking after a history of dependence. ..
  24. Mangues R, Corral T, Lu S, Symmans W, Liu L, Pellicer A. NF1 inactivation cooperates with N-ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity. Oncogene. 1998;17:1705-16 pubmed
  25. Grisart B, Rack K, Vidrequin S, Hilbert P, Deltenre P, Verellen Dumoulin C, et al. NF1 microduplication first clinical report: association with mild mental retardation, early onset of baldness and dental enamel hypoplasia?. Eur J Hum Genet. 2008;16:305-11 pubmed publisher
    ..Similar phenotypic abnormalities were present in most of the individuals, however, two displayed a normal phenotype, suggesting a potential incomplete penetrance of the phenotype associated with NF1 microduplication. ..
  26. Kebudi R, Tuncer S, Upadhyaya M, Peksayar G, Spurlock G, Yazici H. A novel mutation in the NF1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma. Pediatr Blood Cancer. 2008;50:713-5 pubmed
    ..Sequencing of the DNA samples identified a C > T nucleotide change in exon 4b (c484CAG > TAG). This nonsense mutation resulted in a change of glutamine to a stop codon (Q162X) and is a novel NF1 gene alteration. ..
  27. Le L, Parada L. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene. 2007;26:4609-16 pubmed
    ..Therefore, further understanding of the molecular interactions between Schwann cells and their environment will provide tools to develop new therapies aimed at delaying or preventing tumor formation in Nf1 patients. ..
  28. Oguzkan S, Cinbis M, Ayter S, Anlar B, Aysun S. Molecular analysis of neurofibromatosis type 1 in Turkish families using polymorphic markers. Turk J Pediatr. 2003;45:192-7 pubmed
    ..Intragenic microsatellite markers were highly informative for all families. As a result, prenatal and presymptomatic diagnoses for familial cases are being made available. ..
  29. Griffiths S, Thompson P, Frayling I, Upadhyaya M. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6:21-34 pubmed
  30. Rosenbaum T, Engelbrecht V, Krölls W, van Dorsten F, Hoehn Berlage M, Lenard H. MRI abnormalities in neurofibromatosis type 1 (NF1): a study of men and mice. Brain Dev. 1999;21:268-73 pubmed
    ..Therefore, the Nf1 mouse model seems to be unhelpful in providing further insights into the histological basis of hyperintense MRI abnormalities in NF1 patients. ..
  31. Venturin M, Bentivegna A, Moroni R, Larizza L, Riva P. Evidence by expression analysis of candidate genes for congenital heart defects in the NF1 microdeletion interval. Ann Hum Genet. 2005;69:508-16 pubmed
  32. Denayer E, Brems H, De Cock P, Evans G, Van Calenbergh F, Bowers N, et al. Pathogenesis of vestibular schwannoma in ring chromosome 22. BMC Med Genet. 2009;10:97 pubmed publisher
    ..Our findings indicate that patients with a ring 22 should be monitored for NF2-related tumours starting in adolescence. ..
  33. Detjen A, Tinschert S, Kaufmann D, Algermissen B, Nurnberg P, Schuelke M. Analysis of mitochondrial DNA in discordant monozygotic twins with neurofibromatosis type 1. Twin Res Hum Genet. 2007;10:486-95 pubmed
    ..The phenotypic discordance of MZ twins with NF1 cannot be explained by skewed distribution of mtDNA mutations or polymorphisms. ..
  34. Parkin B, Ouillette P, Wang Y, Liu Y, Wright W, Roulston D, et al. NF1 inactivation in adult acute myelogenous leukemia. Clin Cancer Res. 2010;16:4135-47 pubmed publisher
    ..NF1 null states are present in 7 of 95 (7%) of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mammalian target of rapamycin-directed therapeutics. ..
  35. Overdiek A, Winner U, Mayatepek E, Rosenbaum T. Schwann cells from human neurofibromas show increased proliferation rates under the influence of progesterone. Pediatr Res. 2008;64:40-3 pubmed publisher
    ..These data suggest that progesterone plays an important role in the development of neurofibromas in NF1. ..
  36. Venturin M, Gervasini C, Orzan F, Bentivegna A, Corrado L, Colapietro P, et al. Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions. Hum Genet. 2004;115:69-80 pubmed
  37. Gutmann D, Aylsworth A, Carey J, Korf B, Marks J, Pyeritz R, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278:51-7 pubmed
    ..On the basis of the information presented in this review, we propose a comprehensive approach to the diagnosis and treatment of individuals with neurofibromatosis 1 and neurofibromatosis 2. ..
  38. Kehrer Sawatzki H, Schwickardt T, Assum G, Rocchi M, Krone W. A third neurofibromatosis type 1 (NF1) pseudogene at chromosome 15q11.2. Hum Genet. 1997;100:595-600 pubmed
    ..Our findings further support pericentromeric spreading of partial NF1 gene copies at chromosome 15q11.2 during evolution. ..
  39. Bernards A, Snijders A, Hannigan G, Murthy A, Gusella J. Mouse neurofibromatosis type 1 cDNA sequence reveals high degree of conservation of both coding and non-coding mRNA segments. Hum Mol Genet. 1993;2:645-50 pubmed
    ..We have also found that the 3' untranslated segment of NF1 mRNA is highly conserved, suggesting that this region may also be a target for mutations in NF1 patients. ..
  40. Zou M, Butcher D, Sadikovic B, Groves T, Yee S, Rodenhiser D. Characterization of functional elements in the neurofibromatosis (NF1) proximal promoter region. Oncogene. 2004;23:330-9 pubmed
    ..This work provides new information concerning the transcriptional regulation of the NF1 gene, and is the most thorough attempt to date to map functionally relevant regions within the NF1 proximal promoter region. ..
  41. Courtois Cox S, Genther Williams S, Reczek E, Johnson B, McGillicuddy L, Johannessen C, et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006;10:459-72 pubmed
    ..Thus, the ultimate response to the aberrant activation of the Ras pathway is a multifaceted negative feedback signaling network that terminates the oncogenic signal and participates in the senescence response. ..
  42. Buteică E, Stoicescu I, Burada F, Stănoiu B. Genetic and clinical considerations in six cases with neurofibromatosis type 1. Rom J Morphol Embryol. 2007;48:243-8 pubmed
    ..The novo mutations in NF1 gene cause the disease in three cases, and in other three cases, the mutation is inherited (two cases on father side and one case on mother side). ..
  43. Gasparini P, Grifa A, Origone P, Coviello D, Antonacci R, Rocchi M. Detection of a neurofibromatosis type I (NF1) homologous sequence by PCR: implications for the diagnosis and screening of genetic diseases. Mol Cell Probes. 1993;7:415-8 pubmed
    ..An accurate search through several data banks demonstrated that this sequence is a new NF1 homologue. This report shows how it is possible to find homologous sequences at random, and subsequently to make wrong interpretations. ..
  44. Ingram D, Yang F, Travers J, Wenning M, Hiatt K, New S, et al. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J Exp Med. 2000;191:181-8 pubmed
    ..Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types. ..
  45. Ars E, Serra E, Garcia J, Kruyer H, Gaona A, Lazaro C, et al. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet. 2000;9:237-47 pubmed
    ..It is possible that part of the clinical variability in NF1 could be due to mutations affecting mRNA splicing, which is the most common molecular defect in NF1...
  46. Bajenaru M, Zhu Y, Hedrick N, Donahoe J, Parada L, Gutmann D. Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol. 2002;22:5100-13 pubmed
    ..Collectively, our results suggest that loss of neurofibromin is not sufficient for astrocytoma formation in mice and that other genetic or environmental factors might influence NF1-associated glioma tumorigenesis. ..
  47. Jorde L, Watkins W, Viskochil D, O Connell P, Ward K. Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping. Am J Hum Genet. 1993;53:1038-50 pubmed
    ..These are discussed, and guidelines for linkage disequilibrium studies are suggested. ..
  48. Hafezparast M. NF1 mice: smaller brains but no tumours. Trends Mol Med. 2001;7:285 pubmed
  49. van Capelle C, Hogeman P, van der Sijs Bos C, Heggelman B, Idowu B, Slootweg P, et al. Neurofibromatosis presenting with a cherubism phenotype. Eur J Pediatr. 2007;166:905-9 pubmed
    ..This emphasises that cherubism is a clinical phenotype that can be associated with a number of germline mutations involving SH3BP2, PTPN11 and NF1...
  50. Peters H, Hess D, Fahsold R, Schülke M. A novel mutation L1425P in the GAP-region of the NF1 gene detected by temperature gradient gel electrophoresis (TGGE). Mutation in brief no. 230. Online. Hum Mutat. 1999;13:337 pubmed
    ..In contrast to those cases diagnosed with having both GAP-region mutations and malignant tumours, neither the proband nor four clinically affected family members with this mutation showed any evidence of malignancies. ..
  51. Gottfried O, Viskochil D, Couldwell W. Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications. Neurosurg Focus. 2010;28:E8 pubmed publisher
  52. Mattocks C, Baralle D, Tarpey P, ffrench Constant C, Bobrow M, Whittaker J. Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain. J Med Genet. 2004;41:e48 pubmed
  53. Raponi M, Upadhyaya M, Baralle D. Functional splicing assay shows a pathogenic intronic mutation in neurofibromatosis type 1 (NF1) due to intronic sequence exonization. Hum Mutat. 2006;27:294-5 pubmed
    ..Significantly an additional single nucleotide change disrupting the cryptic 5'ss consensus sequence rescues the effect of the pathogenetic mutation resulting in normal splicing. ..