Skip to main content
SpringerLink
Log in

The Germline Mutational Spectrum in Neurofibromatosis Type 1 and Genotype–Phenotype Correlations

  • Chapter
  • First Online:
Neurofibromatosis Type 1

Abstract

Inherited mutations of the NF1 tumour suppressor gene give rise to the tumour predisposition syndrome neurofibromatosis type 1 (NF1). The NF1 gene, located at chromosome 17q11.2, spans 283 kb and contains 61 exons that give rise to a 12-kb mRNA transcript encoding neurofibromin, a key negative regulator of the cellular Ras signalling pathway. The NF1 locus is characterised by one of the highest mutation rates known for any human disorder. Nearly 1,300 different inherited mutations of the NF1 gene have been reported to date as a cause of NF1. These vary in size from deletions spanning more than a megabase to subtle single base-pair substitutions that alter an encoded amino acid or the function of a splice junction. Here, we review the known germline NF1 mutational spectrum and show how the nature, location and frequency of different types of inherited NF1 mutation are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahmadian MR, Kiel C, Stege P, Scheffzek K (2003) Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP. J Mol Biol 329:699–710

    Article  PubMed  CAS  Google Scholar 

  • Ainsworth PJ, Chakraborty PK, Weksberg R (1997) Example of somatic mosaicism in a series of de novo neurofibromatosis type 1 cases due to a maternally derived deletion. Hum Mutat 9:452–457

    Article  PubMed  CAS  Google Scholar 

  • Ars E, Serra E, García J, Kruyer H, Gaona A, Lázaro C, Estivill X (2000) Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet 9:237–247

    Article  PubMed  CAS  Google Scholar 

  • Arun D, Gutmann DH (2004) Recent advances in neurofibromatosis type 1. Curr Opin Neurol 17:101–105

    Article  PubMed  CAS  Google Scholar 

  • Asamoah A, North K, Doran S, Wagstaff J, Ogle R, Collins FS, Korf BR (1995) 17q inversion involving the neurofibromatosis type one locus in a family with neurofibromatosis type one. Am J Med Genet 60:312–316

    Article  PubMed  CAS  Google Scholar 

  • Ball EV, Stenson PD, Abeysinghe SS, Krawczak M, Cooper DN, Chuzhanova NA (2005) Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum Mutat 26:205–213

    Article  PubMed  CAS  Google Scholar 

  • Baralle M, Skoko N, Knezevich A, De Conti L, Motti D, Bhuvanagiri M, Baralle D, Buratti E, Baralle FE (2006) NF1 mRNA biogenesis: effect of the genomic milieu in splicing regulation of the NF1 exon 37 region. FEBS Lett 580:4449–4456

    Article  PubMed  CAS  Google Scholar 

  • Barron VA, Lou H (2012) Alternative splicing of the neurofibromatosis type 1 pre-mRNA. Biosci Rep 32:131–138

    Article  PubMed  CAS  Google Scholar 

  • Bengesser KCD, Steinmann K, Kluwe L, Chuzhanova NA, Wimmer K, Tatagiba M, Tinschert S, Mautner VF, Kehrer-Sawatzki H (2010) A novel third type of recurrent NF1 microdeletion mediated by non-allelic homologous recombination between LRRC37B-containing low-copy repeats in 17q11.2. Hum Mutat 31:742–751

    Article  PubMed  CAS  Google Scholar 

  • Bennett E, Thomas N, Upadhyaya M (2009) Neurofibromatosis type 1: its association with the Ras/MAPK pathway syndromes. J Pediatr Neurol 7:105–115

    CAS  Google Scholar 

  • Ben-Shachar S, Constantini S, Hallevi H, Sach EK, Upadhyaya M, Evans GD, Huson SM (2012) Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation. Eur J Hum Genet. doi:10.1038/ejhg.2012.221

  • Bottillo I, Torrente I, Lanari V, Pinna V, Giustini S, Divona L, De Luca A, Dallapiccola B (2010) Germline mosaicism in neurofibromatosis type 1 due to a paternally derived multi-exon deletion. Am J Med Genet 152A:1467–1473

    PubMed  CAS  Google Scholar 

  • Brems H, Chmara M, Sahbatou M et al (2007) Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis1-like phenotype. Nat Genet 39:1120–1126

    Article  PubMed  CAS  Google Scholar 

  • Casola C, Zekonyte U, Phillips AD, Cooper DN, Hahn MW (2012) Interlocus gene conversion events introduce deleterious mutations into at least 1% of human genes associated with inherited disease. Genome Res 22:429–435

    Article  PubMed  CAS  Google Scholar 

  • Chuzhanova NA, Anassis EJ, Ball EV, Krawczak M, Cooper DN (2003) Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum Mutat 21:28–44

    Article  PubMed  CAS  Google Scholar 

  • Colapietro P, Gervasini C, Natacci F, Rossi L, Riva P, Larizza L (2003) NF1 exon 7 skipping and sequence alterations in exonic splice enhancers (ESEs) in a neurofibromatosis 1 patient. Hum Genet 113:551–554

    Article  PubMed  CAS  Google Scholar 

  • Consoli C, Moss C, Green S, Balderson D, Cooper DN, Upadhyaya M (2005) Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1. J Invest Dermatol 125:463–466

    Article  PubMed  CAS  Google Scholar 

  • Cooper DN (2010) Functional intronic polymorphisms: buried treasure awaiting discovery within our genes. Hum Genomics 4:284–288

    Article  PubMed  Google Scholar 

  • Cooper DN, Mort M, Stenson PD, Ball EV, Chuzhanova NA (2010) Methylation-mediated deamination of 5-methylcytosine appears to give rise to mutations causing human inherited disease in CpNpG trinucleotides, as well as in CpG dinucleotides. Hum Genomics 4:406–410

    Article  PubMed  CAS  Google Scholar 

  • Cooper DN, Bacolla A, Férec C, Vasquez KM, Kehrer-Sawatzki H, Chen JM (2011) On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat 32:1075–1099

    Article  PubMed  CAS  Google Scholar 

  • D’Angelo I, Welti S, Bonneau F, Scheffzek K (2006) A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein. EMBO Rep 7:174–179

    Article  PubMed  CAS  Google Scholar 

  • De Luca A, Bottillo I, Dasdia MC, Morella A, Lanari V, Bernardini L, Divona L, Giustini S, Sinibaldi L, Novelli A, Torrente I, Schirinzi A, Dallapiccola B (2007) Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification. J Med Genet 44:800–808

    Article  PubMed  CAS  Google Scholar 

  • Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet 152A:327–332

    Article  PubMed  CAS  Google Scholar 

  • Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kücükceylan N, Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S, Nürnberg P (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. Am J Hum Genet 66:790–818

    Article  PubMed  CAS  Google Scholar 

  • Fernández-Rodríguez J, Castellsagué J, Benito L, Benavente Y, Capellá G, Blanco I, Serra E, Lázaro C (2011) A mild neurofibromatosis type 1 phenotype produced by the combination of the benign nature of a leaky NF1-splice mutation and the presence of a complex mosaicism. Hum Mutat 32:705–709

    Article  PubMed  CAS  Google Scholar 

  • Forbes SH, Dorschner MO, Le R, Stephens K (2004) Genomic context of paralogous recombination hotspots mediating recurrent NF1 region microdeletion. Genes Chromosomes Cancer 41:12–25

    Article  PubMed  CAS  Google Scholar 

  • Gervasini C, Venturin M, Orzan F, Friso A, Clementi M, Tenconi R, Larizza L, Riva P (2005) Uncommon Alu-mediated NF1 microdeletion with a breakpoint inside the NF1 gene. Genomics 85:273–279

    Article  PubMed  CAS  Google Scholar 

  • Griffiths S, Thompson P, Frayling I et al (2007) Molecular diagnosis for NF1: 2 years experience. Fam Cancer 6:21–34

    Article  PubMed  CAS  Google Scholar 

  • Grisart B, Rack K, Vidrequin S, Hilbert P, Deltenre P, Verellen-Dumoulin C, Destrée A (2008) NF1 microduplication first clinical report: association with mild mental retardation, early onset of baldness and dental enamel hypoplasia? Eur J Hum Genet 16:305–311

    Article  PubMed  CAS  Google Scholar 

  • Gutmann DH, Loehr A, Zhang Y, Kim J, Henkemeyer M, Cashen A (1999) Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation. Oncogene 18:4450–4459

    Article  PubMed  CAS  Google Scholar 

  • Harder A, Titze S, Herbst L, Harder T, Guse K, Tinschert S, Kaufmann D, Rosenbaum T, Mautner VF, Windt E, Wahlländer-Danek U, Wimmer K, Mundlos S, Peters H (2010) Monozygotic twins with neurofibromatosis type 1 (NF1) display differences in methylation of NF1 gene promoter elements, 5′ untranslated region, exon and intron 1. Twin Res Hum Genet 13:582–594

    Article  PubMed  Google Scholar 

  • Horan MP, Osborn M, Cooper DN, Upadhyaya M (2004) Functional analysis of polymorphic variation within the promoter and 5′ untranslated region of the neurofibromatosis type 1 (NF1) gene. Am J Med Genet 131A:227–231

    Article  Google Scholar 

  • Huson SM, Compston DA, Clark P, Harper PS (1989) A genetic study of von Recklinghausen neurofibromatosis in South East Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet 26:704–711

    Article  PubMed  CAS  Google Scholar 

  • Ingram DA, Yang FC, Travers JB, Wenning MJ, Hiatt K, New S, Hood A, Shannon K, Williams DA, Clapp DW (2000) Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J Exp Med 191:181–188

    Article  PubMed  CAS  Google Scholar 

  • Ivanov D, Hamby SE, Stenson PD, Phillips AD, Kehrer-Sawatzki H, Cooper DN, Chuzhanova N (2011) Comparative analysis of germline and somatic microlesion mutational spectra in 17 human tumor suppressor genes. Hum Mutat 32:620–632

    Article  PubMed  CAS  Google Scholar 

  • Jadayel D, Fain P, Upadhyaya M, Ponder MA, Huson SM, Carey J, Fryer A, Mathew CG, Barker DF, Ponder BA (1990) Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 343:558–559

    Article  PubMed  CAS  Google Scholar 

  • Jentarra GM, Rice SG, Olfers S, Rajan C, Saffen DM, Narayanan V (2012) Skewed allele-specific expression of the NF1 gene in normal subjects: a possible mechanism for phenotypic variability in neurofibromatosis type 1. J Child Neurol 27(6):695–702

    Article  PubMed  Google Scholar 

  • Kayes LM, Burke W, Riccardi VM, Bennett R, Ehrlich P, Rubenstein A, Stephens K (1994) Deletions spanning the neurofibromatosis 1 gene: identification and phenotype of five patients. Am J Hum Genet 54:424–436

    PubMed  CAS  Google Scholar 

  • Kehrer-Sawatzki H, Cooper DN (2008) Mosaicism in sporadic neurofibromatosis type 1: variations on a theme common to other hereditary cancer syndromes? J Med Genet 45:622–631

    Article  PubMed  CAS  Google Scholar 

  • Kehrer-Sawatzki H, Häussler J, Krone W, Bode H, Jenne DE, Mehnert KU, Tümmers 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 99:237–247

    Article  PubMed  CAS  Google Scholar 

  • Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF (2004) High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet 75:410–423

    Article  PubMed  CAS  Google Scholar 

  • Kehrer-Sawatzki H, Schmid E, Fünsterer C, Kluwe L, Mautner VF (2008) Absence of cutaneous neurofibromas in an NF1 patient with an atypical deletion partially overlapping the common 1.4 Mb microdeleted region. Am J Med Genet A 146A:691–699

    Article  PubMed  CAS  Google Scholar 

  • Kemkemer R, Schrank S, Vogel W, Gruler H, Kaufmann D (2002) Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 in vitro. Proc Natl Acad Sci USA 99:13783–13788

    Article  PubMed  CAS  Google Scholar 

  • Khaja R, Zhang J, Macdonald JR, He Y, Joseph-George AM, Wei J, Rafiq MA, Qian C, Shago M, Pantano L, Aburatani H, Jones K, Redon R, Hurles M, Armengol L, Estivill X, Mural RJ, Lee C, Scherer SW, Feuk L (2006) Genome assembly comparison identifies structural variants in the human genome. Nat Genet 38:1413–1418

    Article  PubMed  CAS  Google Scholar 

  • Klose A, Ahmadian MR, Schuelke M, Scheffzek K, Hoffmeyer S, Gewies A, Schmitz F, Kaufmann D, Peters H, Wittinghofer A, Nürnberg P (1998) Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum Mol Genet 7:1261–1268

    Article  PubMed  CAS  Google Scholar 

  • Klose A, Peters H, Hoffmeyer S, Buske A, Lüder A, Hess D, Lehmann R, Nürnberg P, Tinschert S (1999) Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet 83:6–12

    Article  PubMed  CAS  Google Scholar 

  • Kluwe L, Tatagiba M, Fünsterer C, Mautner V (2003) NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J Med Genet 40:368–371

    Article  PubMed  CAS  Google Scholar 

  • Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner VF (2004) Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat 23:111–116

    Article  PubMed  CAS  Google Scholar 

  • Krawczak M, Ball EV, Cooper DN (1998) Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am J Hum Genet 63:474–488

    Article  PubMed  CAS  Google Scholar 

  • 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 72:733–738

    Article  PubMed  CAS  Google Scholar 

  • Lázaro C, Ravella A, Gaona A, Volpini V, Estivill X (1994) Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med 331:1403–1407

    Article  PubMed  Google Scholar 

  • Lázaro C, Gaona A, Lynch M, Kruyer H, Ravella A, Estivill X (1995) Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Am J Hum Genet 57:1044–1049

    PubMed  Google Scholar 

  • Lázaro C, Gaona A, Ainsworth P, Tenconi R, Vidaud D, Kruyer H, Ars E, Volpini V, Estivill X (1996) Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum Genet 98:696–699

    Article  PubMed  Google Scholar 

  • Lee J, Jang SJ, Benoit N, Hoque MO, Califano JA, Trink B, Sidransky D, Mao L, Moon C (2010) Presence of 5-methylcytosine in CpNpG trinucleotides in the human genome. Genomics 96:67–72

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Bollag G, Clark R, Stevens J, Conroy L, Fults D, Ward K, Friedman E, Samowitz W, Flobertson M, Bradley P, McCormick F, White R, Cawthon R (1992) Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell 69:261–275

    Google Scholar 

  • Lister R, Pelizzda M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322

    Article  PubMed  CAS  Google Scholar 

  • López-Correa C, Brems H, Lazaro C, Marynen P, Legius E (2000) Unequal meiotic crossover: a frequent cause of NF1 microdeletions. Am J Hum Genet 66:1969–1974

    Article  PubMed  Google Scholar 

  • López-Correa C, Dorschner M, Brems H, Lázaro C, Clementi M, Upadhyaya M, Dooijes D, Moog U, Kehrer-Sawatzki H, Rutkowski JL, Fryns JP, Marynen P, Stephens K, Legius E (2001) Recombination hotspot in NF1 microdeletion patients. Hum Mol Genet 10:1387–1392

    Article  PubMed  Google Scholar 

  • Luijten M, Redeker S, Minoshima S, Shimizu N, Westerveld A, Hulsebos TJ (2001a) Duplication and transposition of the NF1 pseudogene regions on chromosomes 2, 14, and 22. Hum Genet 109:109–116

    Article  PubMed  CAS  Google Scholar 

  • Luijten M, Fahsold R, Mischung C, Westerveld A, Nürnberg P, Hulsebos TJ (2001b) Limited contribution of interchromosomal gene conversion to NF1 gene mutation. J Med Genet 38:481–485

    Article  PubMed  CAS  Google Scholar 

  • Mantripragada KK, Thuresson AC, Piotrowski A, Díaz de Ståhl T, Menzel U, Grigelionis G, Ferner RE, Griffiths S, Bolund L, Mautner V, Nordling M, Legius E, Vetrie D, Dahl N, Messiaen L, Upadhyaya M, Bruder CE, Dumanski JP (2006) Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH. J Med Genet 43:28–38

    Article  PubMed  CAS  Google Scholar 

  • Mattocks C, Baralle D, Tarpey P, ffrench-Constant C, Bobrow M, Whittaker J (2004) 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 41:e48

    Article  PubMed  CAS  Google Scholar 

  • Mautner VF, Kluwe L, Friedrich RE, Roehl AC, Bammert S, Högel J, Spöri H, Cooper DN, Kehrer-Sawatzki H (2010) Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet 47:623–630

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin ME, Jacks T (2002) Thinking beyond the tumor cell. NF1 haploinsufficiency in the tumor environment. Cancer Cell 1:408–410

    Article  PubMed  CAS  Google Scholar 

  • Messiaen LM, Wimmer K (2008) NF1 mutational spectrum. In: Kaufmann D (ed) Neurofibromatoses. Monographs in human genetics, vol 16. Karger, Basel, pp 63–77

    Google Scholar 

  • Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD (2000) Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 15:541–555

    Article  PubMed  CAS  Google Scholar 

  • Messiaen L, Vogt J, Bengesser K, Fu C, Mikhail F, Serra E, Garcia-Linares C, Cooper DN, Lazaro C, Kehrer-Sawatzki H (2011) Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum Mutat 32:213–219

    Article  PubMed  CAS  Google Scholar 

  • Morcos P, Thapar N, Tusneem N, Stacey D, Tamanoi F (1996) Identification of neurofibromin mutants that exhibit allele specificity or increased Ras affinity resulting in suppression of activated ras alleles. Mol Cell Biol 16:2496–2503

    PubMed  CAS  Google Scholar 

  • Mort M, Ivanov D, Cooper DN, Chuzhanova NA (2008) A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat 29:1037–1047

    Article  PubMed  CAS  Google Scholar 

  • Nyström AM, Ekvall S, Strömberg B, Holmström G, Thuresson AC, Annerén G, Bondeson ML (2009) A severe form of Noonan syndrome and autosomal dominant cafe-au-lait spots—evidence for different genetic origins. Acta Paediatr 98:693–698

    Article  PubMed  CAS  Google Scholar 

  • Orzan F, Stroppi M, Venturin M, Valero MC, Hernández C, Riva P (2008) Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele. Neurogenetics 9:95–100

    Article  PubMed  Google Scholar 

  • Osborn M, Cooper DN, Upadhyaya M (2000) Molecular analysis of the 5′-flanking region of the neurofibromatosis type 1 (NF1) gene: identification of five sequence variants. Clin Genet 57:221–224

    Article  PubMed  CAS  Google Scholar 

  • Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bièche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D, Members of the NF France Network (2010) NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat 31:E1506–E1518

    Article  PubMed  CAS  Google Scholar 

  • Pasmant E, Sabbagh A, Masliah-Planchon J, Ortonne N, Laurendeau I, Melin L, Ferkal S, Hernandez L, Leroy K, Valeyrie-Allanore L, Parfait B, Vidaud D, Bièche I, Lantieri L, Wolkenstein P, Vidaud M, Members of the NF France Network (2011) Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst 103:1713–1722

    Article  PubMed  CAS  Google Scholar 

  • Pemov A, Park C, Reilly KM, Stewart DR (2010) Evidence of perturbations of cell cycle and DNA repair pathways as a consequence of human and murine NF1-haploinsufficiency. BMC Genomics 11:194

    Article  PubMed  CAS  Google Scholar 

  • Petek E, Jenne DE, Smolle J, Binder B, Lasinger W, Windpassinger C, Wagner K, Kroisel PM, Kehrer-Sawatzki H (2003) Mitotic recombination mediated by the JJAZF1 (KIAA0160) gene causing somatic mosaicism and a new type of constitutional NF1 microdeletion in two children of a mosaic female with only few manifestations. J Med Genet 40:520–525

    Article  PubMed  CAS  Google Scholar 

  • Poullet P, Lin B, Esson K, Tamanoi F (1994) Functional significance of lysine 1423 of neurofibromin and characterization of a second site suppressor which rescues mutations at this residue and suppresses RAS2Val-19- activated phenotypes. Mol Cell Biol 14:815–821

    PubMed  CAS  Google Scholar 

  • Pros E, Gómez C, Martín T, Fábregas P, Serra E, Lázaro C (2008) Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat 29:E173–E193

    Article  PubMed  Google Scholar 

  • Raedt TD, Stephens M, Heyns I, Brems H, Thijs D, Messiaen L, Stephens K, Lazaro C, Wimmer K, Kehrer-Sawatzki H, Vidaud D, Kluwe L, Marynen P, Legius E (2006) Conservation of hotspots for recombination in low-copy repeats associated with the NF1 microdeletion. Nat Genet 38:1419–1423

    Article  PubMed  CAS  Google Scholar 

  • Raponi M, Upadhyaya M, Baralle D (2006) Functional splicing assay shows a pathogenic intronic mutation in neurofibromatosis type 1 (NF1) due to intronic sequence exonization. Hum Mutat 27:294–295

    Article  PubMed  CAS  Google Scholar 

  • Rodenhiser DI, Andrews JD, Mancini DN, Jung JH, Singh SM (1997) Homonucleotide tracts, short repeats and CpG/CpNpG motifs are frequent sites for heterogeneous mutations in the neurofibromatosis type 1 (NF1) tumour-suppressor gene. Mutat Res 373:185–195

    Article  PubMed  CAS  Google Scholar 

  • Roehl AC, Vogt J, Mussotter T, Zickler AN, Spöti H, Högel J, Chuzhanova NA, Wimmer K, Kluwe L, Mautner VF, Cooper DN, Kehrer-Sawatzki H (2010) Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions. Hum Mutat 31:1163–1173

    Article  PubMed  CAS  Google Scholar 

  • Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, Combemale P, Ferkal S, Vidaud M, Aubourg P, Vidaud D, Wolkenstein P, Members of the NF France Network (2009) Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet 18:2768–2778

    Article  PubMed  CAS  Google Scholar 

  • Scheffzek K, Ahmadian MR, Kabsch W, Wiesmüller L, Lautwein A, Schmitz F, Wittinghofer A (1997) The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277:333–338

    Article  PubMed  CAS  Google Scholar 

  • Scheffzek K, Ahmadian MR, Wiesmüller L, Kabsch W, Stege P, Schmitz F, Wittinghofer A (1998) Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J 17:4313–4327

    Article  PubMed  CAS  Google Scholar 

  • Sharif S, Upadhyaya M, Ferner R, Majounie E, Shenton A, Baser M, Thakker N, Evans DG (2011) A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations. J Med Genet 48:256–260

    Article  PubMed  CAS  Google Scholar 

  • Skinner RH, Bradley S, Brown AL, Johnson NJE, Rhodes S, Stammers DK, Lowe PN (1991) Use of the Glu-Glu-Phe C-terminal epitope for rapid purification of the catalytic domain of normal and mutant ras GTPase-activating proteins. J Biol Chem 266:14163–14166

    PubMed  CAS  Google Scholar 

  • Spiegel M, Oexle K, Horn D, Windt E, Buske A, Albrecht B, Prott EC, Seemanová E, Seidel J, Rosenbaum T, Jenne D, Kehrer-Sawatzki H, Tinschert S (2005) Childhood overgrowth in patients with common NF1 microdeletions. Eur J Hum Genet 13:883–888

    Article  PubMed  CAS  Google Scholar 

  • Spits C, De Rycke M, Van Ranst N et al (2005) Preimplantation genetic diagnosis for neurofibromatosis type 1. Mol Hum Reprod 11:381–387

    Article  PubMed  CAS  Google Scholar 

  • Steinmann K, Cooper DN, Kluwe L, Chuzhanova NA, Senger C, Serra E, Lazaro C, Gilaberte M, Wimmer K, Mautner VF, Kehrer-Sawatzki H (2007) Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination. Am J Hum Genet 81:1201–1220

    Article  PubMed  CAS  Google Scholar 

  • Steinmann K, Kluwe L, Cooper DN, Brems H, De Raedt T, Legius E, Mautner VF, Kehrer-Sawatzki H (2008) Copy number variations in the NF1 gene region are infrequent and do not predispose to recurrent type-1 deletions. Eur J Hum Genet 16:572–580

    Article  PubMed  CAS  Google Scholar 

  • Stenson PD, Mort M, Ball EV, Howells K, Phillips AD, Thomas NS, Cooper DN (2009) The human gene mutation database: 2008 update. Genome Med 1:13

    Article  PubMed  CAS  Google Scholar 

  • Stephens K, Kayes L, Riccardi VM, Rising M, Sybert VP, Pagon RA (1992) Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum Genet 88:279–282

    Article  PubMed  CAS  Google Scholar 

  • Sterne-Weiler T, Howard J, Mort M, Cooper DN, Sanford JR (2011) Loss of exon identity is a common mechanism of human inherited disease. Genome Res 21:1563–1571

    Article  PubMed  CAS  Google Scholar 

  • Takano T, Kawashima T, Yamanouchi Y, Kitayama K, Baba T, Ueno K, Hamaguchi H (1992) Genetics of neurofibromatosis 1 in Japan: mutation rate and paternal age effect. Hum Genet 89:281–286

    Article  PubMed  CAS  Google Scholar 

  • Thomas L, Richards M, Mort M, Dunlop E, Cooper DN, Upadhyaya M (2012) Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene. Hum Mutat 33:1687–1696

    Google Scholar 

  • Trovó-Marqui AB, Tajara EH (2006) Neurofibromin: a general outlook. Clin Genet 70:1–13

    Article  PubMed  Google Scholar 

  • Upadhyaya M (2008) NF1 gene structure and NF1 genotype/phenotype correlations. In: Kaufmann D (ed) The neurofibromatoses. Karger, Basel, pp 46–62

    Chapter  Google Scholar 

  • Upadhyaya M, Osborn MJ, Maynard J, Kim MR, Tamanoi F, Cooper DN (1997) Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Hum Genet 99:88–92

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA, Krawczak M, Cooper DN (1998) Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum Genet 102:591–597

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Majounie E, Thompson P, Han S, Consoli C, Krawczak M, Cordeiro I, Cooper DN (2003) Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet 112:12–17

    Article  PubMed  CAS  Google Scholar 

  • 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 (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. Am J Hum Genet 80:140–151

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Spurlock G, Kluwe L, Chuzhanova N, Bennett E, Thomas N, Guha A, Mautner V (2009) The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 10:251–263

    Article  PubMed  CAS  Google Scholar 

  • Valero MC, Martín Y, Hernández-Imaz E, Marina Hernández A, Meleán G, Valero AM, Javier Rodríguez-Álvarez F, Tellería D, Hernández-Chico C (2011) A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn 13:113–122

    Article  PubMed  CAS  Google Scholar 

  • Venturin M, Gervasini C, Orzan F, Bentivegna A, Corrado L, Colapietro P, Friso A, Tenconi R, Upadhyaya M, Larizza L, Riva P (2004) Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions. Hum Genet 115:69–80

    Article  PubMed  CAS  Google Scholar 

  • Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O’Connell P (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62:187–192

    Article  PubMed  CAS  Google Scholar 

  • Wallace MR, Andersen LB, Saulino AM, Gregory PE, Glover TW, Collins FS (1991) A de novo Alu insertion results in neurofibromatosis type 1. Nature 353:864–866

    Article  PubMed  CAS  Google Scholar 

  • Welti S, Fraterman S, D’Angelo I, Wilm M, Scheffzek K (2007) The sec14 homology module of neurofibromin binds cellular glycerophospholipids: mass spectrometry and structure of a lipid complex. J Mol Biol 366:551–562

    Article  PubMed  CAS  Google Scholar 

  • Welti S, D’Angelo I, Scheffzek K (2008) Structure and function of neurofibromin. In: Neurofibromatoses. Monographs in human genetics, vol 16. Basel, Karger, pp 113–128

    Google Scholar 

  • Welti S, Kühn S, D’Angelo I, Brügger B, Kaufmann D, Scheffzek K (2011) Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin. Hum Mutat 32:191–197

    Article  PubMed  CAS  Google Scholar 

  • Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglböck H, Maertens O, Messiaen L (2006) Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer 45:265–276

    Article  PubMed  CAS  Google Scholar 

  • Wimmer K, Roca X, Beiglböck H, Callens T, Etzler J, Rao AR, Krainer AR, Fonatsch C, Messiaen L (2007) Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5′ splice-site disruption. Hum Mutat 28:599–612

    Article  PubMed  CAS  Google Scholar 

  • Wimmer K, Callens T, Wernstedt A, Messiaen L (2011) The NF1 gene contains hotspots for L1 endonuclease-dependent de novo insertion. PLoS Genet 7:e1002371

    Article  PubMed  CAS  Google Scholar 

  • Wong KK, Deleeuw RJ, Dosanjh NS, Kimm LR, Cheng Z, Horsman DE, Macaulay C, Ng RT, Brown CJ, Eichler EE, Lam WL (2007) A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 80:91–104

    Article  PubMed  CAS  Google Scholar 

  • Xu H, Gutmann DH (1997) Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules. Brain Res 759:149–152

    Article  PubMed  CAS  Google Scholar 

  • Yu H, Zhao X, Su B, Li D, Xu Y, Luo S, Xiao C, Wang W (2005) Expression of NF1 pseudogenes. Hum Mutat 26:487–488

    Article  PubMed  CAS  Google Scholar 

  • Zatkova A, Messiaen L, Vandenbroucke I, Wieser R, Fonatsch C, Krainer AR, Wimmer K (2004) Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1. Hum Mutat 24:491–501

    Article  PubMed  CAS  Google Scholar 

  • Zickler AM, Hampp S, Messiaen L, Bengesser K, Mussotter T, Roehl AC, Wimmer K, Mautner VF, Kluwe L, Upadhyaya M, Pasmant E, Chuzhanova N, Kestler HA, Högel J, Legius E, Claes K, Cooper DN, Kehrer-Sawatzki H (2012) Characterization of the nonallelic homologous recombination hotspot PRS3 associated with type-3 NF1 deletions. Hum Mutat 33:372–383

    Article  PubMed  CAS  Google Scholar 

  • Zlotogora J (1998) Germ line mosaicism. Hum Genet 102:381–386

    Article  PubMed  CAS  Google Scholar 

  • Zou MX, Butcher DT, Sadikovic B, Groves TC, Yee SP, Rodenhiser DI (2004) Characterization of functional elements in the neurofibromatosis (NF1) proximal promoter region. Oncogene 23:330–339

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

    David N. Cooper & Meena Upadhyaya

Authors
  1. David N. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meena Upadhyaya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meena Upadhyaya .

Editor information

Editors and Affiliations

  1. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park Campus, Cardiff, 144XN, United Kingdom

    Meena Upadhyaya

  2. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom

    David N. Cooper

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Cooper, D.N., Upadhyaya, M. (2012). The Germline Mutational Spectrum in Neurofibromatosis Type 1 and Genotype–Phenotype Correlations. In: Upadhyaya, M., Cooper, D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32864-0_10

Download citation

Publish with us

Policies and ethics

Search

Navigation