Skip to main content

Advertisement

SpringerLink
Log in

The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas

  • Original Article
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

Neurofibromatosis type 1 (NF1) is a common inherited complex multi-system disorder associated with the growth of various benign and malignant tumors. About 40% of NF1 patients develop spinal tumors, of whom some have familial spinal neurofibromatosis (FSNF), a variant form of NF1 in which patients present with multiple bilateral spinal tumors but have few other clinical features of the disease. We have studied 22 spinal neurofibromas derived from 14 unrelated NF1 patients. Seven of these patients satisfied the diagnostic criteria of NF1 while the remaining seven had only few features of NF1. The latter group defined as FSNF harbored significantly higher number of missense or missense and splice-site germline mutations compared to the group with classical NF1. This is the first study to describe NF1 somatic mutations in spinal neurofibromas. Loss-of-heterozygosity (LOH) was identified in 8/22 of the spinal tumors, 75% of LOH observed was found to result from mitotic recombination, suggesting that this may represent a frequent mutational mechanisms in these benign tumors. No evidence for LOH of the TP53 gene was found in these tumors.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. 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 neurofibroma associated with a 3-bp in-frame 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(1):140–151. doi:10.1086/510781

    Article  PubMed  CAS  Google Scholar 

  2. Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A (2007) Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44:81–88. doi:10.1136/jmg.2006.045906

    Article  PubMed  CAS  Google Scholar 

  3. Thakkar SD, Feigen U, Mautner VF (1999) Spinal tumours in neurofibromatosis type 1: an MRI study of frequency, multiplicity and variety. Neuroradiologie 41:625–629. doi:10.1007/s002340050814

    Article  CAS  Google Scholar 

  4. Mautner VF, Asuagbor FA, Dombi E, Fünsterer C, Kluwe L, Wenzel R, Widemann BC, Friedman JM (2008) Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro-oncol 10:593–598. doi:10.1215/15228517-2008-011

    Article  PubMed  Google Scholar 

  5. Kluwe L, Tatagiba M, Fünsterer C, Mautner VF (2003) NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J Med Genet 40(5):368–371. doi:10.1136/jmg.40.5.368

    Article  PubMed  CAS  Google Scholar 

  6. Pulst SM, Riccardi VM, Fain P, Korenberg JR (1991) Familial spinal neurofibromatosis: clinical and DNA linkage analysis. Neurology 41:1923–1925

    PubMed  CAS  Google Scholar 

  7. Ars E, Kruyer H, Gaona A, Casquero P, Rosell J, Volpini V, Serra E, Lazaro C, Estivill X (1998) A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene. Am J Hum Genet 62:834–841. doi:10.1086/301803

    Article  PubMed  CAS  Google Scholar 

  8. Poyhonen M, Leisti EL, Kytölä S, Leisti J (1997) Hereditary spinal neurofibromatosis: a rare form of NF1? J Med Genet 34:184–187. doi:10.1136/jmg.34.3.184

    Article  PubMed  CAS  Google Scholar 

  9. Kaufmann D, Müller R, Bartelt B, Wolf M, Kunzi-Rapp K, Hanemann CO, Fahsold R, Hein C, Vogel W, Assum G (2001) Spinal neurofibromatosis without café-au-lait macules in two families with null mutations of the NF1 gene. Am J Hum Genet 69:1395–1400. doi:10.1086/324648

    Article  PubMed  CAS  Google Scholar 

  10. Wimmer K, Mühlbauer M, Eckart M, Callens T, Rehder H, Birkner T, Leroy JG, Fonatsch C, Messiaen L (2002) A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene. Eur J Hum Genet 10:334–338. doi:10.1038/sj.ejhg.5200807

    Article  PubMed  Google Scholar 

  11. Messiae L, Riccardi V, Peltonen J, Maertens O, Callens T, Karvonen SL, Leisti E-L, Koivunen J, Vandenbroucke I, Stephens K, Pöyhönen M (2003) Independent NF1 mutations in two large families with spinal neurofibromatosis. J Med Genet 40:122–126. doi:10.1136/jmg.40.2.122

    Article  Google Scholar 

  12. Messiaen L, Callens T, Williams JB Babovic-Vuksanovic, Huson S, Legius E, Mac Gardner R, Pascual-Castroviejo I, Plotkin S, Scaefer GB, Wilson M, Korf B (2007) Genotype-phenotype correlations in spinal NF. [Abstract 985] Presented at the annual meeting of The American Society of Human Genetics, October 25, 2007, San Diego, California. Available from: http://www.ashg.org/genetics/ashg07s/index.shtml

  13. Upadhyaya M, Kluwe L, Spurlock G, Mantripragada K, Monem B, Majounie E, Ruggieri M, Chuzhanova N, Evan DG, Ferner R, Thomas N, Guha A, Mautner V (2008) The germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumours (MPNST). Hum Mutat 29:74–82. doi:10.1002/humu.20601

    Article  PubMed  CAS  Google Scholar 

  14. Upadhyaya M, Spurlock G, Monem B, Thomas N, Friedrich RE, Kluwe L, Mautner V (2008) Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat 29(8):E103−E111. Online publication.

    Google Scholar 

  15. Upadhyaya M, Han S, Consoli C, Majounie E, Horan M, Thomas N, Potts C, Griffiths S, Ruggieri M, von Deimling A, Cooper DN (2004) Characterisation of somatic mutational spectrum of neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumours. Hum Mutat 23:134–146. doi:10.1002/humu.10305

    Article  PubMed  CAS  Google Scholar 

  16. Griffiths S, Thompson P, Frayling I, Upadhyaya M (2006) Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer 6:21–34. doi:10.1007/s10689-006-9001-3

    Article  Google Scholar 

  17. Futreal PA, Barrett JC, Wiseman RW (1991) An Alu polymorphism intragenic to the TP53 gene. Nucleic Acids Res 19:6977. doi:10.1093/nar/19.24.6977

    Article  PubMed  CAS  Google Scholar 

  18. Legius E, Herman D, Wu R, Hall BK, Marynen P, Cassiman J (1994) TP53 mutations are frequent in malignant NF1 tumours. Gene Chromosome Canc 10:250–255. doi:10.1002/gcc.2870100405

    Article  CAS  Google Scholar 

  19. Abeysinghe SS, Chuzhanova N, Krawczak M, Ball EV, Cooper DN (2003) Translocation and gross deletion breakpoints in human inherited disease and cancer I: nucleotide composition and recombination-associated motifs. Hum Mutat 22:229–244. doi:10.1002/humu.10254

    Article  PubMed  CAS  Google Scholar 

  20. Ball EV, Stenson PD, Krawczak M, Cooper DN, Chuzhanova NA (2005) Micro-deletions and micro-insertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum Mutat 26:205–213. doi:10.1002/humu.20212

    Article  PubMed  CAS  Google Scholar 

  21. Bacolla A, Jaworski A, Larson JE, Jakupciak JP, Chuzhanova N, Abeysinghe SS, O'Connell CD, Cooper DN, Wells RD (2004) Breakpoints of gross deletions coincide with non-B DNA conformations. Proc Natl Acad Sci USA 101:14162–14167. doi:10.1073/pnas.0405974101

    Article  PubMed  CAS  Google Scholar 

  22. Gusev VD, Nemytikova LA, Chuzhanova NA (1999) On the complexity measures of genetic sequences. Bioinformatics 15:994–999. doi:10.1093/bioinformatics/15.12.994

    Article  PubMed  CAS  Google Scholar 

  23. Chuzhanova NA, Anassis EJ, Ball E, 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. doi:10.1002/humu.10146

    Article  PubMed  CAS  Google Scholar 

  24. Maertens O, De Schepper S, Vandesompele J, Heyns I, Janssens S, Speleman F, Legius E, Messiaen L (2007) Molecular dissection of isolated disease features in neurofibromatosis type 1. Am J Hum Genet 81:243–251. doi:10.1086/519562

    Article  PubMed  CAS  Google Scholar 

  25. 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(3):410–423. doi:10.1086/423624

    Article  PubMed  CAS  Google Scholar 

  26. Kehrer-Sawatzki H, Kluwe L, Fünsterer C, Mautner VF (2005) Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCR-mediated 2-Mb deletion in 17q11.2. Hum Genet 116:466–475. doi:10.1007/s00439-005-1265-4

    Article  PubMed  CAS  Google Scholar 

  27. Dorschner MO, Sybert VP, Weaver M, Pletcher BA, Stephens K (2000) NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum Mol Genet 9:35–46. doi:10.1093/hmg/9.1.35

    Article  PubMed  CAS  Google Scholar 

  28. Kehrer-Sawatzki H, Tinschert S, Jenne DE (2003) Heterogeneity of breakpoints in non-LCR-mediated large constitutional deletions of the 17q11.2 NF1 tumour suppressor region. J Med Genet 40:E116. doi:10.1136/jmg.40.10.e116

    Article  PubMed  CAS  Google Scholar 

  29. Colman SD, Williams CA, Wallace MR (1995) Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nat Genet 11:90–92. doi:10.1038/ng0995-90

    Article  PubMed  CAS  Google Scholar 

  30. Eisenbarth I, Beyer K, Krone W, Assum G (2000) Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1. Am J Hum Genet 66:393–401. doi:10.1086/302747

    Article  PubMed  CAS  Google Scholar 

  31. Serra E, Ars E, Ravella A, Sanchez A, Puig S, Rosenbaum T, Estivill X, Lazaro C (2001) Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations. Hum Genet 108:416–429. doi:10.1007/s004390100514

    Article  PubMed  CAS  Google Scholar 

  32. Maertens O, Brems H, Vandesompele J, De Raedt T, Heyns I, Rosenbaum T, De Schepper S, De Paepe A, Mortier G, Janssens S, Speleman F, Legius E, Messiaen L (2006) Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum Mutat 27:1030–1040. doi:10.1002/humu.20389

    Article  PubMed  CAS  Google Scholar 

  33. Spurlock G, Griffiths S, Uff J, Upadhyaya M (2007) Somatic alterations of the NF1 gene in an NF1 individual with multiple benign tumours (internal and external) and malignant tumour types. Fam Cancer 6:463–471. doi:10.1007/s10689-007-9149-5

    Article  PubMed  CAS  Google Scholar 

  34. Serra E, Rosenbaum T, Nadal M, Winner U, Ars E, Estivill X, Lazaro C (2001) Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas. Nat Genet 28:294–296. doi:10.1038/90148

    Article  PubMed  CAS  Google Scholar 

  35. De Raedt T, Maertens O, Brems H, Heyns I, Sciot R, Majounie E, Upadhyaya M, Speleman F, Messiaen L, Vermeesch JR, Legius E (2006) Loss of heterozygosity in neurofibromas: comparison of NF1 microdeletion and non-microdeletion patients. Gene Chromosome Canc 45:893–904. doi:10.1002/gcc.20353

    Article  Google Scholar 

  36. Zheng H, Chang L, Patel N, Yang J, Lowe L, Burns DK, Zhu Y (2008) Induction of abnormal proliferation by non-myelinating schwann cells triggers neurofibroma formation. Cancer Cell 13:117–128.

    Article  PubMed  CAS  Google Scholar 

  37. Birindelli S, Perrone F, Oggionni M, Lavarino C, Pasini B, Vergani B, Ranzani GN, Pierotti MA, Pilotti S (2001) Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumours. Lab Invest 81:833–844

    PubMed  CAS  Google Scholar 

  38. Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Botella P, Viaño J (2007) Familial spinal neurofibromatosis. Neuropediatrics 38(2):105–108. doi:10.1055/s-2007-985136

    Article  PubMed  CAS  Google Scholar 

  39. 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. doi:10.1002/humu.9412

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Cancer Research UK for financial support. We are grateful to all the patients and their families who have contributed to this study.

Author information

Authors and Affiliations

  1. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, Cf14 4XN, UK

    Meena Upadhyaya, Gill Spurlock, Emma Bennett & Nick Thomas

  2. Laboratory for Tumor Biology and Developmental Disorders, Department of Maxillofacial Surgery, University Hospital Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Lan Kluwe & Victor Mautner

  3. Department of Biological Sciences, University of Central Lancashire, Preston, UK

    Nadia Chuzhanova

  4. Hospital for Sick Children, University of Toronto, Western Hospital, Toronto, Ontario, Canada

    Abhijit Guha

Authors
  1. Meena Upadhyaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gill Spurlock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lan Kluwe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadia Chuzhanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emma Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nick Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Abhijit Guha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Victor Mautner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meena Upadhyaya.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Upadhyaya, M., Spurlock, G., Kluwe, L. et al. The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 10, 251–263 (2009). https://doi.org/10.1007/s10048-009-0178-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-009-0178-0

Keywords

Search

Navigation