Human Genetics

, Volume 118, Issue 5, pp 551–558

The neurobeachin gene spans the common fragile site FRA13A

  • Larissa Savelyeva
  • Evgeny Sagulenko
  • Jens Guido Schmitt
  • Manfred Schwab
Original Investigation

Abstract

Common fragile sites are normal constituents of chromosomal structure prone to chromosomal breakage. In humans, the cytogenetic locations of more than 80 common fragile sites are known. The DNA at 11 of them has been defined and characterized at the molecular level. According to the Genome Database, the common fragile site FRA13A maps to chromosome band 13q13.2. Here, we identify the precise genomic position of FRA13A, and characterize the genetic complexity of the fragile DNA sequence. We show that FRA13A breaks are limited to a 650 kb region within the neurobeachin (NBEA) gene, which genomically spans approximately 730 kb. NBEA encodes a neuron-specific multidomain protein implicated in membrane trafficking that is predominantly expressed in the brain and during development.

Keywords

Chromosomal instability Common fragile sites FRA13A Neurobeachin NBEA Autism 

References

  1. Arlt MF, Miller DE, Beer DG, Glover TW (2002) Molecular characterization of FRAXB and comparative common fragile site instability in cancer cells. Genes Chromosomes Cancer 33:82–92CrossRefPubMedGoogle Scholar
  2. Arlt MF, Casper AM, Glover TW (2003) Common fragile sites. Cytogenet Genome Res 100:92–100CrossRefPubMedGoogle Scholar
  3. Arlt MF, Xu B, Durkin SG, Casper AM, Kastan MB, Glover TW (2004) BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function. Mol Cell Biol 24:6701–6709CrossRefPubMedGoogle Scholar
  4. Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL, Childress D, et al (1999) An autosomal genomic screen for autism. Collaborative linkage study of autism. Am J Med Genet 88:609–615CrossRefPubMedGoogle Scholar
  5. Bednarek AK, Keck-Waggoner CL, Daniel RL, Laflin KJ, Bergsagel PL, Kiguchi K, Brenner AJ, Aldaz CM (2001) WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res 61:8068–8073PubMedGoogle Scholar
  6. Boldog FL, Waggoner B, Glover TW, Chumakov I, Le Paslier D, Cohen D, Gemmill RM, Drabkin HA (1994) Integrated YAC contig containing the 3p14.2 hereditary renal carcinoma 3;8 translocation breakpoint and the fragile site FRA3B. Genes Chromosomes Cancer 11:216–221PubMedCrossRefGoogle Scholar
  7. Buttel I, Fechter A, Schwab M (2004) Common fragile sites and cancer: targeted cloning by insertional mutagenesis. Ann NY Acad Sci 1028:14–27CrossRefPubMedGoogle Scholar
  8. Casper AM, Nghiem P, Arlt MF, Glover TW (2002) ATR regulates fragile site stability. Cell 111:779–789CrossRefPubMedGoogle Scholar
  9. Castermans D, Wilquet V, Parthoens E, Huysmans C, Steyaert J, Swinnen L, Fryns JP, Van de Ven W, Devriendt K (2003) The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism. J Med Genet 40:352–356PubMedCrossRefGoogle Scholar
  10. Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H, Trapasso F, Drusco A, Shimizu M, Masciullo V, D’Andrilli G, Scambia G, Picchio MC, Alder H, Godwin AK, Croce CM (2003) Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27. Proc Natl Acad Sci USA 100:5956–5961CrossRefPubMedGoogle Scholar
  11. Ciullo M, Debily MA, Rozier L, Autiero M, Billault A, Mayau V, El Marhomy S, Guardiola J, Bernheim A, Coullin P, Piatier-Tonneau D, Debatisse M (2002) Initiation of the breakage-fusion-bridge mechanism through common fragile site activation in human breast cancer cells: the model of PIP gene duplication from a break at FRA7I. Hum Mol Genet 23:2887–2894CrossRefGoogle Scholar
  12. Denison SR, Callahan G, Becker NA, Phillips LA, Smith DI (2003) Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Genes Chromosomes Cancer 38:40–52CrossRefPubMedGoogle Scholar
  13. Glover TW, Berger C, Coyle J, Echo B (1984) DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67:136–142CrossRefPubMedGoogle Scholar
  14. Hellman A, Rahat A, Scherer SW, Darvasi A, Tsui LC, Kerem B (2000) Replication delay along FRA7H, a common fragile site on human chromosome 7, leads to chromosomal instability. Mol Cell Biol 20:4420–4427CrossRefPubMedGoogle Scholar
  15. Henegariu O, Bray-Ward P, Ward DC (2000) Custom fluorescent-nucleotide synthesis as an alternative method for nucleic acid labeling. Nat Biotechnol 18:345–348CrossRefPubMedGoogle Scholar
  16. Huang H, Qian J, Proffit J, Wilber K, Jenkins R, Smith DI (1998) FRA7G extends over a broad region: coincidence of human endogenous retroviral sequences (HERV-H) and small polydispersed circular DNAs (spcDNA) and fragile sites. Oncogene 16:2311–2319PubMedCrossRefGoogle Scholar
  17. Huebner K, Croce CM (2001) FRA3B and other common fragile sites: the weakest links. Nat Rev Cancer 1:214–221CrossRefPubMedGoogle Scholar
  18. Le Beau MM, Rassool FV, Neilly ME, Espinosa R III, Glover TW, Smith DI, McKeithan TW (1998) Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Hum Mol Genet 7:755–761PubMedCrossRefGoogle Scholar
  19. Limongi MZ, Pelliccia F, Rocchi A (2003) Characterization of the human common fragile site FRA2G. Genomics 81:93–97CrossRefPubMedGoogle Scholar
  20. Mangelsdorf M, Ried K, Woollatt E, Dayan S, Eyre H, Finnis M, Hobson L, Nancarrow J, Venter D, Baker E, Richards RI (2000) Chromosomal fragile site FRA16D and DNA instability in cancer. Cancer Res 60:1683–1689PubMedGoogle Scholar
  21. Margolis RL, Stine OC, McInnis MG, Ranen NG, Rubinsztein DC, Leggo J, Brando LV, Kidwai AS, Loev SJ, Breschel TS, Callahan C, Simpson SG, DePaulo JR, McMahon FJ, Jain S, Paykel ES, Walsh C, DeLisi LE, Crow TJ, Torrey EF, Ashworth RG, Macke JP, Nathans J, Ross CA (1996) cDNA cloning of a human homologue of the Caenorhabditis elegans cell fate-determining gene mab-21: expression, chromosomal localization and analysis of a highly polymorphic (CAG)n trinucleotide repeat. Hum Mol Genet 5:607–616PubMedCrossRefGoogle Scholar
  22. Mariani M, Baldessari D, Francisconi S, Viggiano L, Rocchi M, Zappavigna V, Malgaretti N, Consalez GG (1999) Two murine and human homologs of mab-21, a cell fate determination gene involved in Caenorhabditis elegans neural development. Hum Mol Genet 8:2397–2406CrossRefPubMedGoogle Scholar
  23. Matzner I, Savelyeva L, Schwab M (2003) Preferential integration of a transfected marker gene into spontaneously expressed fragile sites of a breast cancer cell line. Cancer Lett 189:207–219CrossRefPubMedGoogle Scholar
  24. Mimori K, Druck T, Inoue H, Alder H, Berk L, Mori M, Huebner K, Croce CM (1999) Cancer-specific chromosome alterations in the constitutive fragile region FRA3B. Proc Natl Acad Sci USA 96:7456–7461CrossRefPubMedGoogle Scholar
  25. Mishmar D, Rahat A, Scherer SW, Nyakatura G, Hinzmann B, Kohwi Y, Mandel-Gutfroind Y, Lee JR, Drescher B, Sas DE, Margalit H, Platzer M, Weiss A, Tsui LC, Rosenthal A, Kerem B (1998) Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site. Proc Natl Acad Sci USA 95:8141–8146CrossRefPubMedGoogle Scholar
  26. Morelli C, Karayianni E, Magnanini C, Mungall AJ, Thorland E, Negrini M, Smith DI, Barbanti-Brodano G (2002) Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene 21:7266–7276CrossRefPubMedGoogle Scholar
  27. Munteanu MG, Vlahovicek K, Parthasarathy S, Simon I, Pongor S (1998) Rod models of DNA: sequence-dependent anisotropic elastic modelling of local bending phenomena. Trends Biochem Sci 23:341–347CrossRefPubMedGoogle Scholar
  28. Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K (1996) The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84:587–597CrossRefPubMedGoogle Scholar
  29. Paradee W, Wilke CM, Wang L, Shridhar R, Mullins CM, Hoge A, Glover TW, Smith DI (1996) A 350-kb cosmid contig in 3p14.2 that crosses the t (3;8) hereditary renal cell carcinoma translocation breakpoint and 17 aphidicolin-induced FRA3B breakpoints. Genomics 35:87–93CrossRefPubMedGoogle Scholar
  30. Rassool FV, Le Beau MM, Shen ML, Neilly ME, Espinosa R III, Ong ST, Boldog F, Drabkin H, McCarroll R, McKeithan TW (1996) Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2. Genomics 35:109–117CrossRefPubMedGoogle Scholar
  31. Richards RI (2001) Fragile and unstable chromosomes in cancer: causes and consequences. Trends Genet 17:339–345CrossRefPubMedGoogle Scholar
  32. Ried K, Finnis M, Hobson L, Mangelsdorf M, Dayan S, Nancarrow JK, Woollatt E, Kremmidiotis G, Gardner A, Venter D, Baker E, Richards RI (2000) Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells. Hum Mol Genet 9:1651–1663CrossRefPubMedGoogle Scholar
  33. Rozier L, El-Achkar E, Apiou F, Debatisse M (2004) Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer. Oncogene 23:6872–6880CrossRefPubMedGoogle Scholar
  34. Smit AF (1999) Interspersed repeats and other mementos of transposable elements in mammalian genomes. Curr Opin Genet Dev 9:657–663CrossRefPubMedGoogle Scholar
  35. Su Y, Balice-Gordon RJ, Hess DM, Landsman DS, Minarcik J, Golden J, Hurwitz I, Liebhaber SA, Cooke NE (2004) Neurobeachin is essential for neuromuscular synaptic transmission. J Neurosci 24:3627–3636CrossRefPubMedGoogle Scholar
  36. Sutherland GR (2003) Rare fragile sites. Cytogenet Genome Res 100:77–84CrossRefPubMedGoogle Scholar
  37. Sutherland GR, Baker E (2000) The clinical significance of fragile sites on human chromosomes. Clin Genet 58:157–161CrossRefPubMedGoogle Scholar
  38. Wang L, Darling J, Zhang JS, Huang H, Liu W, Smith DI (1999) Allele-specific late replication and fragility of the most active common fragile site, FRA3B. Hum Mol Genet 8:431–437CrossRefPubMedGoogle Scholar
  39. Wang X, Herberg FW, Laue MM, Wullner C, Hu B, Petrasch-Parwez E, Kilimann MW (2000) Neurobeachin: a protein kinase A-anchoring, beige/Chediak-higashi protein homolog implicated in neuronal membrane traffic. J Neurosci 20:8551–8565PubMedGoogle Scholar
  40. Wilke CM, Guo SW, Hall BK, Boldog F, Gemmill RM, Chandrasekharappa SC, Barcroft CL, Drabkin HA, Glover TW (1994) Multicolour FISH mapping of YAC clones in 3p14 and identification of a YAC spanning both FRA3B and the t (3;8) associated with hereditary renal cell carcinoma. Genomics 22:319–326CrossRefPubMedGoogle Scholar
  41. Zimonjic DB, Druck T, Ohta M, Kastury K, Croce CM, Popescu NC, Huebner K (1997) Positions of chromosome 3p14.2 fragile sites (FRA3B) within the FHIT gene. Cancer Res 57:1166–1170PubMedGoogle Scholar
  42. Zlotorynski E, Rahat A, Skaug J, Ben-Porat N, Ozeri E, Hershberg R, Levi A, Scherer SW, Margalit H, Kerem B (2003) Molecular basis for expression of common and rare fragile sites. Mol Cell Biol 23:7143–7151CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Larissa Savelyeva
    • 1
  • Evgeny Sagulenko
    • 1
  • Jens Guido Schmitt
    • 1
  • Manfred Schwab
    • 1
  1. 1.Division of Tumor GeneticsGerman Cancer Research CenterHeidelbergGermany

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