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Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation

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Abstract

The hallmark of neurofibromatosis type 1 (NF1) are multiple dermal neurofibromas. They show high inter- and intrafamilial variability for which the influence of modifying genes is discussed. NF1 patients presenting microdeletions spanning NF1 and several contiguous genes have an earlier onset and higher number of dermal neurofibromas than classical NF1 patients, pointing to one of the deleted genes as modifier. Expression analysis of 13 genes of the microdeletion region in dermal neurofibromas and other tissues revealed four candidates for the modification of neurofibroma formation: CENTA2, RAB11FIP4, C17orf79, and UTP6.

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References

  1. Rasmussen SA, Friedman JM (2000) NF1 gene and neurofibromatosis 1. Am J Epidemiol 151:33–40

    Article  CAS  PubMed  Google Scholar 

  2. Easton DF, Ponder MA, Huson SM, Ponder BA (1993) An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet 53:305–313

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wiest V, Eisenbarth I, Schmegner C, Krone W, Assum G (2003) Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers. Hum Mutat 22:423–427 doi:10.1002/humu.10272

    Article  CAS  PubMed  Google Scholar 

  4. Fishbein L, Zhang X, Fisher LB, Li H, Campbell-Thompson M, Yachnis A et al (2007) In vitro studies of steroid hormones in neurofibromatosis 1 tumors and Schwann cells. Mol Carcinog 46:512–523 doi:10.1002/mc.20236

    Article  CAS  PubMed  Google Scholar 

  5. Clementi M, Boni S, Mammi I, Favarato M, Tenconi R (1996) Clinical application of genetic polymorphism in neurofibromatosis type 1. Ann Genet 39:92–96

    CAS  PubMed  Google Scholar 

  6. Cnossen MH, van der Est MN, Breuning MH, van Asperen CJ, Breslau-Siderius EJ, van der Ploeg AT et al (1997) Deletions spanning the neurofibromatosis type 1 gene: implications for genotype–phenotype correlations in neurofibromatosis type 1. Hum Mutat 9:458–464 doi:10.1002/(SICI)1098-1004(1997)9:5<458::AID-HUMU13>3.0.CO;2-1

    Article  CAS  PubMed  Google Scholar 

  7. Rasmussen SA, Colman SD, Ho VT, Abernathy CR, Arn PH, Weiss L et al (1998) Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1. J Med Genet 35:468–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H et al (2004) Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat 23:111–116 doi:10.1002/humu.10299

    Article  CAS  PubMed  Google Scholar 

  9. Mensink KA, Ketterling RP, Flynn HC, Knudson RA, Lindor NM, Heese BA et al (2006) Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature. J Med Genet 43:e8 doi:10.1136/jmg.2005.034256

    Article  CAS  PubMed  Google Scholar 

  10. Jenne DE, Tinschert S, Dorschner MO, Hameister H, Stephens K, Kehrer-Sawatzki H (2003) Complete physical map and gene content of the human NF1 tumor suppressor region in human and mouse. Genes Chromosomes Cancer 37:111–120 doi:10.1002/gcc.10206

    Article  CAS  PubMed  Google Scholar 

  11. De Raedt T, Brems H, Lopez-Correa C, Vermeesch JR, Marynen P, Legius E (2004) Genomic organization and evolution of the NF1 microdeletion region. Genomics 84:346–360 doi:10.1016/j.ygeno.2004.03.006

    Article  PubMed  Google Scholar 

  12. Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T (2003) New microRNAs from mouse and human. RNA 9:175–179 doi:10.1261/rna.2146903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O et al (2005) Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37:766–770 doi:10.1038/ng1590

    Article  CAS  PubMed  Google Scholar 

  14. Lopez CC, 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 doi:10.1086/302920

    Article  Google Scholar 

  15. Venturin M, Guarnieri P, Natacci F, Stabile M, Tenconi R, Clementi M et al (2004) Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2. J Med Genet 41:35–41 doi:10.1136/jmg.2003.014761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Venturin M, Bentivegna A, Moroni R, Larizza L, Riva P (2005) Evidence by expression analysis of candidate genes for congenital heart defects in the NF1 microdeletion interval. Ann Hum Genet 69:508–516 doi:10.1111/j.1529-8817.2005.00203.x

    Article  CAS  PubMed  Google Scholar 

  17. Douglas J, Cilliers D, Coleman K, Tatton-Brown K, Barker K, Bernhard B et al (2007) Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Nat Genet 39:963–965 doi:10.1038/ng2083

    Article  CAS  PubMed  Google Scholar 

  18. Riccardi VM (2007) The genetic predisposition to and histogenesis of neurofibromas and neurofibrosarcoma in neurofibromatosis type 1. Neurosurg Focus 22:E3 doi:10.3171/foc.2007.22.6.4

    Article  PubMed  Google Scholar 

  19. Yang FC, Ingram DA, Chen S, Hingtgen CM, Ratner N, Monk KR et al (2003) Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/− mast cells. J Clin Invest 112:1851–1861 doi:10.1172/JCI200319195

    Article  CAS  PubMed  Google Scholar 

  20. Yang FC, Chen S, Clegg T, Li X, Morgan T, Estwick SA et al (2006) Nf1+/− mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling. Hum Mol Genet 15:2421–2437 doi:10.1093/hmg/ddl165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kirshenbaum AS, Akin C, Wu Y, Rottem M, Goff JP, Beaven MA et al (2003) Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of FcepsilonRI or FcgammaRI. Leuk Res 27:677–682 doi:10.1016/S0145-2126(02)00343-0

    Article  CAS  PubMed  Google Scholar 

  22. Kluwe L, Friedrich RE, Mautner VF (1999) Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas. Cancer Genet Cytogenet 113:65–69 doi:10.1016/S0165-4608(99)00006-0

    Article  CAS  PubMed  Google Scholar 

  23. 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  CAS  PubMed  PubMed Central  Google Scholar 

  24. Radonic A, Thulke S, Mackay IM, Landt O, Siegert W, Nitsche A (2004) Guideline to reference gene selection for quantitative real-time PCR. Biochem Biophys Res Commun 313:856–862 doi:10.1016/j.bbrc.2003.11.177

    Article  CAS  PubMed  Google Scholar 

  25. Rutledge RG, Cote C (2003) Mathematics of quantitative kinetic PCR and the application of standard curves. Nucleic Acids Res 31:e93 doi:10.1093/nar/gng093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Venkateswarlu K, Brandom KG, Yun H (2007) PI-3-kinase-dependent membrane recruitment of centaurin-alpha2 is essential for its effect on ARF6-mediated actin cytoskeleton reorganisation. J Cell Sci 120:792–801 doi:10.1242/jcs.03373

    Article  CAS  PubMed  Google Scholar 

  27. Tague SE, Muralidharan V, D'Souza-Schorey C (2004) ADP-ribosylation factor 6 regulates tumor cell invasion through the activation of the MEK/ERK signaling pathway. Proc Natl Acad Sci U S A 101:9671–9676 doi:10.1073/pnas.0403531101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fielding AB, Schonteich E, Matheson J, Wilson G, Yu X, Hickson GR et al (2005) Rab11-FIP3 and FIP4 interact with Arf6 and the exocyst to control membrane traffic in cytokinesis. EMBO J 24:3389–3399 doi:10.1038/sj.emboj.7600803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Piddubnyak V, Rigou P, Michel L, Rain JC, Geneste O, Wolkenstein P et al (2007) Positive regulation of apoptosis by HCA66, a new Apaf-1 interacting protein, and its putative role in the physiopathology of NF1 microdeletion syndrome patients. Cell Death Differ 14:1222–1233 doi:10.1038/sj.cdd.4402122

    Article  CAS  PubMed  Google Scholar 

  30. Lacroix M, Messaoudi SE, Rodier G, Le Cam A, Sardet C, Fabbrizio E (2008) The histone-binding protein COPR5 is required for nuclear functions of the protein arginine methyltransferase PRMT5. EMBO Rep 9:452–458 doi:10.1038/embor.2008.45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Drs. Berlien, Hamideh, Müller, Riedel (Dept. of Lasermedicine, Elisabeth-Klinik, Berlin), Kunzi-Rapp (ILM, Ulm), Baezner, Hein (Dept. of Neurosurgery, University Hospital Ulm), and Tinschert (Institute for Clinical Genetics, Technical University Dresden) for supplying tissue samples and H. Goetz, A. Siegel, A. Schwandt, and H. Spoeri of our institute for the expert technical assistance. This work was supported by grant no. KA 898/6-1 from DFG. The authors declare that the experiments of this work comply with the current German laws.

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  1. Institute of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    B. Bartelt-Kirbach, M. Wuepping, M. Dodrimont-Lattke & D. Kaufmann

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  1. B. Bartelt-Kirbach
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  2. M. Wuepping
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Correspondence to D. Kaufmann.

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Bartelt-Kirbach, B., Wuepping, M., Dodrimont-Lattke, M. et al. Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation. Neurogenetics 10, 79–85 (2009). https://doi.org/10.1007/s10048-008-0154-0

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  • DOI: https://doi.org/10.1007/s10048-008-0154-0

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