Insights into NF1 from Evolution

  • Britta Bartelt-Kirbach
  • Dieter Kaufmann


The gene product of NF1, neurofibromin, is a very large protein. The known functional domains (GRD, Sec14 and PH-like domain) account for only about 20 % of the size. Comparison of human neurofibromin with its homologues from various species led to the detection of the presently known domains and maybe will also help to identify further functional regions of this protein. Evolutionary comparisons also revealed that NF1 is a very old gene with its origin in the fungi/metazoa ancestor, which is approximately 1,200 million years old. A strong evolutionary constraint has to lie on neurofibromin function as the gene structure and exon organisation are conserved even between human and ray-finned fish (Takifugu rupripes) and almost no change is observed in primate evolution. In addition to the coding sequence also, the NF1 genomic region exhibits very little change during primate evolution. In contrast, the region of the three genes inserted in an NF1 intron, OMG, EVI2A and EVI2B, seems to be more variable.


Neurospora Crassa Oligodendrocyte Myelin Glycoprotein Ensembl Database Ecotropic Viral Integration Site Isochore Structure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Assum G, Schmegner C (2008) NF1 gene in evolution. In: Kaufmann D (ed) Neurofibromatoses, vol 16, Monographs in human genetics. Karger, Basel, pp 103–112CrossRefGoogle Scholar
  2. Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63(4):851–859PubMedCrossRefGoogle Scholar
  3. Bernardi G (2000) Isochores and the evolutionary genomics of vertebrates. Gene 241:3–17PubMedCrossRefGoogle Scholar
  4. Bernards A, Snijders AJ, Hannigan GE, Murthy AE, Gusella JF (1993) Mouse neurofibromatosis type 1 cDNA sequence reveals high degree of conservation of both coding and non-coding mRNA segments. Hum Mol Genet 2(6):645–650PubMedCrossRefGoogle Scholar
  5. Buchberg AM, Bedigian HG, Jenkins NA, Copeland NG (1990) Evi-2, a common integration site involved in murine myeloid leukemogenesis. Mol Cell Biol 10(9):4658–4666PubMedGoogle Scholar
  6. Cawthon RM, O’Connell P, Buchberg AM, Viskochil D, Weiss RB, Culver M, Stevens J, Jenkins NA, Copeland NG, White R (1990) Identification and characterization of transcripts from the neurofibromatosis 1 region: the sequence and genomic structure of EVI2 and mapping of other transcripts. Genomics 7(4):555–565PubMedCrossRefGoogle Scholar
  7. Cawthon RM, Andersen LB, Buchberg AM, Xu GF, O’Connell P, Viskochil D, Weiss RB, Wallace MR, Marchuk DA, Culver M et al (1991) cDNA sequence and genomic structure of EV12B, a gene lying within an intron of the neurofibromatosis type 1 gene. Genomics 9(3):446–460PubMedCrossRefGoogle Scholar
  8. Costantini M, Clay O, Auletta F, Bernardi G (2006) An isochore map of human chromosomes. Genome Res 16:536–541PubMedCrossRefGoogle Scholar
  9. Cunningham LA, Coté AG, Cam-Ozdemir C, Lewis SM (2003) Rapid, stabilizing palindrome rearrangements in somatic cells by the center-break mechanism. Mol Cell Biol 23:8740–8750PubMedCrossRefGoogle Scholar
  10. D’Angelo I, Welti S, Bonneau F, Scheffzek K (2006) A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein. EMBO Rep 7(2):174–179PubMedCrossRefGoogle Scholar
  11. Eisenbarth I, Vogel G, Krone W, Vogel W, Assum G (2000) An isochore transition in the NF1 gene region coincides with a switch in the extent of linkage disequilibrium. Am J Hum Genet 67:873–880PubMedCrossRefGoogle Scholar
  12. Farah JA, Hartsuiker E, Mizuno K, Ohta K, Smith GR (2002) A 160-bp palindromic is a Rad50 Rad32-dependent mitotic recombination hotspot in Schizosaccharomyces pombe. Genetics 161:461–468PubMedGoogle Scholar
  13. Feng DF, Cho G, Doolittle RF (1997) Determining divergence times with a protein clock: update and reevaluation. Proc Natl Acad Sci USA 94(24):13028–13033PubMedCrossRefGoogle Scholar
  14. Gao Q, Jin K, Ying SH, Zhang Y, Xiao G, Shang Y, Duan Z, Hu X, Xie XQ, Zhou G, Peng G, Luo Z, Huang W, Wang B, Fang W, Wang S, Zhong Y, Ma LJ, St Leger RJ, Zhao GP, Pei Y, Feng MG, Xia Y, Wang C (2011) Genome sequencing and comparative transcriptomics of the model entomopathogenic fungi Metarhizium anisopliae and M. acridum. PLoS Genet 7(1):e1001264PubMedCrossRefGoogle Scholar
  15. Gutmann DH, Wood DL, Collins FS (1991) Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci USA 88(21):9658–9662PubMedCrossRefGoogle Scholar
  16. Golovnina K, Blinov A, Chang LS (2006) Evolution and origin of neurofibromin, the product of the neurofibromatosis type 1 (NF1) tumor-suppressor gene. BGRS 3(5):142–146Google Scholar
  17. Inagaki H, Ohye T, Kogo H, Yamada K, Kowa H, Shaikh TH, Emanuel BS, Kurahashi H (2005) Palindromic AT-rich repeat in the NF1 gene is hypervariable in humans and evolutionarily conserved in primates. Hum Mutat 26(4):332–342PubMedCrossRefGoogle Scholar
  18. Jeffries TW, Grigoriev IV, Grimwood J, Laplaza JM, Aerts A, Salamov A, Schmutz J, Lindquist E, Dehal P, Shapiro H, Jin YS, Passoth V, Richardson PM (2007) Genome sequence of the lignocellulose-bioconverting and xylose-fermenting yeast Pichia stipitis. Nat Biotechnol 25(3):319–326PubMedCrossRefGoogle Scholar
  19. Kehrer-Sawatzki H, Haussler J, Krone W, Bode H, Jenne DE, Mehnert KU, Tummers U, Assum G (1997) The second case of a t(17;22) in a family with neurofibromatosis type 1: sequence analysis of the breakpoint regions. Hum Genet 99:237–247PubMedCrossRefGoogle Scholar
  20. Kehrer-Sawatzki H, Maier C, Moschgath E, Elgar G, Krone W (1998) Genomic characterization of the neurofibromatosis type 1 gene of Fugu rubripes. Gene 222(1):145–153PubMedCrossRefGoogle Scholar
  21. Kurahashi H, Shaikh T, Takata M, Toda T, Emanuel BS (2003) The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats. Am J Hum Genet 72:733–738PubMedCrossRefGoogle Scholar
  22. Mikol DD, Alexakos MJ, Bayley CA, Lemons RS, Le Beau MM, Stefansson K (1990) Structure and chromosomal localization of the gene for the oligodendrocyte-myelin glycoprotein. J Cell Biol 111(6 Pt 1):2673–2679PubMedCrossRefGoogle Scholar
  23. Mikol DD, Rongnoparut P, Allwardt BA, Marton LS, Stefansson K (1993) The oligodendrocyte-myelin glycoprotein of mouse: primary structure and gene structure. Genomics 17(3):604–610PubMedCrossRefGoogle Scholar
  24. O’Connell P, Viskochil D, Buchberg AM, Fountain J, Cawthon RM, Culver M, Stevens J, Rich DC, Ledbetter DH, Wallace M et al (1990) The human homolog of murine Evi-2 lies between two von Recklinghausen neurofibromatosis translocations. Genomics 7(4):547–554PubMedCrossRefGoogle Scholar
  25. Saavedra RA, Fors L, Aebersold RH, Arden B, Horvath S, Sanders J, Hood L (1989) The myelin proteins of the shark brain are similar to the myelin proteins of the mammalian peripheral nervous system. J Mol Evol 29(2):149–156PubMedCrossRefGoogle Scholar
  26. Schmegner C, Berger A, Vogel W, Hameister H, Assum G (2005a) An isochore transition zone in the NF1 gene region is a conserved landmark of chromosome structure and function. Genomics 86:439–445PubMedCrossRefGoogle Scholar
  27. Schmegner C, Hoegel J, Vogel W, Assum G (2005b) Genetic variability in a genomic region with long-range linkage disequilibrium reveals traces of a bottleneck in the history of the European population. Hum Genet 118:276–286PubMedCrossRefGoogle Scholar
  28. Schmegner C, Hameister H, Vogel W, Assum G (2007) Isochores and replication time zones: a perfect match. Cytogenet Genome Res 116:167–172PubMedCrossRefGoogle Scholar
  29. The I, Hannigan GE, Cowley GS, Reginald S, Zhong Y, Gusella JF, Hariharan IK, Bernards A (1997) Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science 276(5313):791–794PubMedCrossRefGoogle Scholar
  30. Viskochil D, Cawthon R, O’Connell P, Xu GF, Stevens J, Culver M, Carey J, White R (1991) The gene encoding the oligodendrocyte-myelin glycoprotein is embedded within the neurofibromatosis type 1 gene. Mol Cell Biol 11(2):906–912PubMedGoogle Scholar
  31. Vourc’h P, Moreau T, Arbion F, Marouillat-Védrine S, Müh JP, Andres C (2003) Oligodendrocyte myelin glycoprotein growth inhibition function requires its conserved leucine-rich repeat domain, not its glycosylphosphatidyl-inositol anchor. J Neurochem 85(4):889–897PubMedCrossRefGoogle Scholar
  32. Waehneldt TV (1990) Phylogeny of myelin proteins. Ann N Y Acad Sci 605:15–28PubMedCrossRefGoogle Scholar
  33. Wohlbach DJ, Kuo A, Sato TK, Potts KM, Salamov AA, Labutti KM, Sun H, Clum A, Pangilinan JL, Lindquist EA, Lucas S, Lapidus A, Jin M, Gunawan C, Balan V, Dale BE, Jeffries TW, Zinkel R, Barry KW, Grigoriev IV, Gasch AP (2011) Comparative genomics of xylose-fermenting fungi for enhanced biofuel production. Proc Natl Acad Sci USA 108(32):13212–13217PubMedCrossRefGoogle Scholar
  34. Xu G, O’Connell P, Stevens J, White R (1992) Characterization of human adenylate kinase 3 (AK3) cDNA and mapping of the AK3 pseudogene to an intron of the NF1 gene. Genomics 13(3):537–542PubMedCrossRefGoogle Scholar
  35. Yoshida M, Colman DR (1996) Parallel evolution and coexpression of the proteolipid proteins and protein zero in vertebrate myelin. Neuron 16(6):1115–1126PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Institute of Anatomy and Cell BiologyUniversity of UlmUlmGermany
  2. 2.Institute of Human GeneticsUniversity of UlmUlmGermany

Personalised recommendations