Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome

Nature Genetics volume 17, pages 154–163 (1997)Cite this article

Abstract

Smith–Magenis syndrome (SMS), caused by del(17)p11.2, represents one of the most frequently observed human microdeletion syndromes. We have identified three copies of a low–copy–number repeat (SMS–REPs) located within and flanking the SMS common deletion region and show that SMS–REP represents a repeated gene cluster. We have isolated a corresponding cDNA clone that identifies a novel junction fragment from 29 unrelated SMS patients and a different–sized junction fragment from a patient with dup(17)p11.2. Our results suggest that homologous recombination of a flanking repeat gene cluster is a mechanism for this common microdeletion syndrome.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Krawczak, M. & Cooper, D.N. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum. Genet. 86, 425–441 (1991).

    CAS  PubMed  Google Scholar 

  2. Peeters, B.P.H., de Boer, J.H., Bron, S. & Venema, G. Structural plasmid instability in Bacillus subtilis: effect of direct and inverted repeats. Mol. Gen. Genet. 212, 450–458 (1988).

    CAS  PubMed  Google Scholar 

  3. Singer, B.S. & Westlye, J. Deletion formation in bacteriophage T4. J. Mol. Biol. 202, 233–243 (1988).

    CAS  PubMed  Google Scholar 

  4. Whoriskey, S.K., Schofield, M.A. & Miller, J.H. Isolation and characterization of Escherichia coli mutants with altered rates of deletion formation. Genetics 127, 21–30 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Greenberg, F. et al. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am. J. Hum. Genet. 49, 1207–1218 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Smith, A.C.M. et al. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am. J. Med. Genet. 24, 393–414 (1986).

    CAS  PubMed  Google Scholar 

  7. Stratton, R.F. et al. Interstitial deletion of (17)(p11.2p11.2): report of six additional patients with a new chromosome deletion syndrome. Am. J. Med. Genet. 24, 421–432 (1986).

    CAS  PubMed  Google Scholar 

  8. Greenberg, F. et al. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am. J. Med. Genet. 62, 247–254 (1996).

    CAS  PubMed  Google Scholar 

  9. Chen, K.-S., Potocki, L. & Lupski, J.R. Smith-Magenis syndrome [del(17)p11.2]: clinical review and molecular advances. Ment. Retard. Dev. Disabil. Res. Rev. 2, 122–129 (1996).

    Google Scholar 

  10. Guzzetta, V. et al. Somatic cell hybrids, sequence-tagged sites, simple repeat polymorphisms, and yeast artificial chromosomes for physical and genetic mapping of proximal 17p. Genomics 13, 551–559 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Juyal, R.C. et al. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am. J. Hum. Genet. 58, 998–1007 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Trask, B.J. et al. Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients. Hum. Genet. 98, 710–718 (1996).

    CAS  PubMed  Google Scholar 

  13. Ledbetter, D.H. & Ballabio, A. Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage imbalance. in The Metabolic and Molecular Bases of Inherited Disease, 7th Ed., Vol. 1 (eds Scriver, C.R., Beaudet, A.L, Sly, W.S. & Valle, D.) 811–839 (McGraw-Hill, New York, (1995).

    Google Scholar 

  14. Guzzetta, V., Montes de Oca-Luna, R., Lupski, J.R. & Patel, P.I. Isolation of region-specific and polymorphic markers from chromosome 17 by restricted Alu polymerase chain reaction. Genomics 9, 31–36 (1991).

    CAS  PubMed  Google Scholar 

  15. Bellanné-Chantelot, C. et al. Mapping the whole human genome by fingerprinting yeast artificial chromosomes. Cell 70, 1059–1068 (1992).

    PubMed  Google Scholar 

  16. Albertsen, H.M. et al. Construction and characterization of a yeast artificial chromosome library containing seven haploid human genome equivalents. Proc. Natl. Acad. Sci. USA 87, 4256–4260 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Murray, J.C. et al. A comprehensive human linkage map with centimorgan density. Science 265, 2049–2054 (1994).

    CAS  PubMed  Google Scholar 

  18. Green, E.D. & Olson, M.V. Systematic screening of yeast artificial-chromosome libraries by use of the polymerase chain reaction. Proc. Natl. Acad. Sci. USA 87, 1213–1217 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kwiatkowski, T.J.J., Zoghbi, H.Y., Ledbetter, S.A., Ellison, K.A. & Chinault, A.C. Rapid identification of yeast artificial chromosome clones by matrix pooling and crude lysate PCR. Nucleic Acids Res. 18, 7191–7192 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chumakov, I.M. et al. Isolation of chromosome 21-specific yeast artificial chromosomes from a total human genome library. Nature Genet. 1, 222–225 (1992).

    CAS  PubMed  Google Scholar 

  21. Chumakov, I. et al. Continuum of overlapping clones spanning the entire human chromosome 21q. Nature 359, 380–387 (1992).

    CAS  PubMed  Google Scholar 

  22. Herz, J., Flint, N., Stanley, K., Frank, R. & Dobberstein, B. The 68 kDa protein of signal recognition particle contains a glycine-rich region also found in certain RNA-binding proteins. FEBS Lett. 276, 103–107 (1990).

    CAS  PubMed  Google Scholar 

  23. Nakamura, T. et al. A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells. Oncogene 7, 733–741 (1992).

    CAS  PubMed  Google Scholar 

  24. Chevillard, C. et al. Relationship between Charcot-Marie-Tooth 1A and Smith-Magenis regions: snU3 may be a candidate gene for the Smith-Magenis syndrome. Hum. Mol. Genet. 2, 1235–1243 (1993).

    CAS  PubMed  Google Scholar 

  25. Kallioniemi, O.-P. et al. Physical mapping of chromosome 17 cosmids by fluorescence in situ hybridization and digital image analysis. Genomics 20, 125–128 (1994).

    CAS  PubMed  Google Scholar 

  26. Lee, C.C. et al. Isolation of chromosome-specific genes by reciprocal probing of arrayed cDNA and cosmid libraries. Hum. Mol. Genet. 8, 1373–1380 (1995).

    Google Scholar 

  27. de Hostos, E.L., Bradtke, B., Lottspeich, F. & Gerisch, G. Coactosin, a 17 kDa F-actin binding protein from Dictyostelium discoideum. Cell. Motil. Cytoskeleton 26, 181–191 (1993).

    CAS  PubMed  Google Scholar 

  28. Wu, C., Friedlander, P., Lamoureux, C., Zannis-Hadjopoulos, M. & Price, G.B. cDNA clones contain autonomous replication activity. Biochim. Biophys. Acta 1174, 241–257 (1993).

    CAS  PubMed  Google Scholar 

  29. Shaffer, L.G., Kennedy, G.M., Spikes, A.S. & Lupski, J.R. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am. J. Med. Genet. 69, 325–331 (1997).

    CAS  PubMed  Google Scholar 

  30. Scheurlen, W.G. et al. High-resolution deletion mapping of chromosome arm 17p in childhood primitive neuroectodermal tumors reveals a common chromosomal disruption within the Smith-Magenis region, an unstable region in chromosome band 17p11.2. Genes Chromosomes Cancer 18, 50–58 (1997).

    CAS  PubMed  Google Scholar 

  31. Wilgenbus, K.K. et al. Molecular characterization of a genetically unstable region containing the SMS critical area and a breakpoint cluster for human PNETs. Genomics 42, 1–10 (1997).

    CAS  PubMed  Google Scholar 

  32. Lifton, R.P. et al. A chimaeric 11β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–265 (1992).

    CAS  PubMed  Google Scholar 

  33. Melki, J. et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 264, 1474–1477 (1994).

    CAS  PubMed  Google Scholar 

  34. Roy, N. et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80, 167–178 (1995).

    CAS  PubMed  Google Scholar 

  35. Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).

    CAS  PubMed  Google Scholar 

  36. Ballabio, A., Bardoni, B., Guioli, S., Basler, E. & Camerino, G. Two families of low-copy-number repeats are interspersed on Xp22. 3: implications for the high frequency of deletions in this region. Genomics 8, 263–270 (1990).

    CAS  PubMed  Google Scholar 

  37. Yen, P.H. et al. Frequent deletions of the human X chromosome distal short arm result form recombination between low copy repetitive elements. Cell 61, 603–610 (1990).

    CAS  PubMed  Google Scholar 

  38. Li, X.-M., Yen, P.H. & Shapiro, L.J. Characterization of a low copy repetitive element S232 involved in the generation of frequent deletions of the distal short arm of the human X chromosome. Nucleic Acids Res. 20, 1117–1122 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Nathans, J., Piantanida, T.P., Eddy, R.L., Shows, T.B. & Hogness, D.S. Molecular genetics of inherited variation in human color vision. Science 232, 203–210 (1986).

    CAS  PubMed  Google Scholar 

  40. Maniatis, T., Fritsch, E.F., Lauer, J. & Lawn, R.M. The molecular genetics of human hemoglobins. Annu. Rev. Genet. 14, 145–178 (1980).

    CAS  PubMed  Google Scholar 

  41. Lakich, D., Kazazian, H.H., Antonarakis, S.E. Jr., & Gitschier, J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature Genet. 5, 236–241 (1993).

    CAS  PubMed  Google Scholar 

  42. Juyal, R.C. et al. Apparent mosaicism for del(17)(p11.2) ruled out by fluorescence in situ hybridization in a Smith-Magenis syndrome patient. Am. J. Med. Genet. 59, 406–407 (1995).

    CAS  PubMed  Google Scholar 

  43. Juyal, R.C. et al. Smith-Magenis syndrome deletion: a case with equivocal cytogenetic findings resolved by fluorescence in situ hybridization. Am. J. Med. Genet. 58, 286–291 (1995).

    CAS  PubMed  Google Scholar 

  44. Zori, R.T. et al. Clinical, cytogenetic, and molecular evidence for an infant with Smith-Magenis syndrome born from a mother having a mosaic 17p11.2p12 deletion. Am. J. Med. Genet. 47, 504–511 (1993).

    CAS  PubMed  Google Scholar 

  45. Botto, M. et al. Homozygous hereditary C3 deficiency due to a partial gene deletion. Proc. Natl. Acad. Sci. USA 89, 4957–4961 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lehrman, M.A., Russell, D.W., Goldstein, J.L. & Brown, M.S. Alu-Alu recombination deletes splice acceptor sites and produces secreted low density lipoprotein receptor in a subject with familial hypercholesterolemia. J. Biol. Chem. 262, 3354–3361 (1987).

    CAS  PubMed  Google Scholar 

  47. Kmiec, E.B., Angelides, K.J. & Holloman, W.K. Left-handed DNA and the synaptic pairing reaction promoted by Ustilago Red protein. Cell 40, 139–145 (1985).

    CAS  PubMed  Google Scholar 

  48. Pentao, L., Wise, C.A., Chinault, A.C., Patel, P.I. & Lupski, J.R. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nature Genet. 2, 292–300 (1992).

    CAS  PubMed  Google Scholar 

  49. Chance, P.F. et al. Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17. Hum. Mol. Genet. 3, 223–228 (1994).

    CAS  PubMed  Google Scholar 

  50. Roa, B.B. & Lupski, J.R. Molecular genetics of Charcot-Marie-Tooth neuropathy, in Advances in Human Genetics, Vol. 22 (eds Harris, H. & Hirschhorn, K.) 117–152 (Plenum, New York, (1994).

    Google Scholar 

  51. Reiter, L.T. et al. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nature Genet. 12, 288–297 (1996).

    CAS  PubMed  Google Scholar 

  52. LeGuern, E. et al. A de novo case of hereditary neuropathy with liability to pressure palsies (HNPP) of maternal origin: a new mechanism for deletion in 17p11.2? Hum. Mol. Genet. 5, 103–106 (1996).

    CAS  PubMed  Google Scholar 

  53. Jones, C. et al. Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature 376, 145–149 (1995).

    CAS  PubMed  Google Scholar 

  54. Roa, B.B. et al. Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1 A neuropathy. Hum. Genet. 97, 642–649 (1996).

    CAS  PubMed  Google Scholar 

  55. Reiter, L.T., Murakami, T., Koeuth, T., Gibbs, R.A. & Lupski, J.R. The human COX10 gene is disrupted during homologous recombination between the 24-Kb proximal and distal CMT1 A-REPs. Hum. Mol. Genet. 6, 1595–1603 (1997).

    CAS  PubMed  Google Scholar 

  56. Halford, S. et al. Low-copy-number repeat sequences flank the DiGeorge/velo-cardio-facial syndrome loci at 22q11. Hum. Mol. Genet. 2, 191–196 (1993).

    CAS  PubMed  Google Scholar 

  57. Ji, Y. et al. An evolutionary conserved gene associated with the common deletion breakpoint regions in the Prader-Willi/Angelman syndromes. Am. J. Hum. Genet. 59, A158 (1996).

    Google Scholar 

  58. Christian, S.L. et al. Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients. Am. J. Hum. Genet. 57, 40–48 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Pérez, L.A., Peoples, R., Kaplan, P., Hamel, B.C.J. & Francke, U. Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth. Am. J. Hum. Genet. 59, 781–792 (1996).

    Google Scholar 

  60. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    CAS  PubMed  Google Scholar 

  61. Evans, G.A., Lewis, K. & Rothenberg, B.E. High efficiency vectors for cosmid microcloning and genomic analysis. Gene 79, 9–20 (1989).

    CAS  PubMed  Google Scholar 

  62. Brownstein, B.H. et al. Isolation of single-copy human genes from a library of yeast artificial chromosome clones. Science 244, 1348–1351 (1989).

    CAS  PubMed  Google Scholar 

  63. Ochman, H., Gerber, A.S. & Hartl, D.L. Genetic applications of an inverse polymerase chain reaction. Genetics 120, 621–623 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Silverman, G.A. et al. Yeast artificial chromosome cloning of a two-megabase-size contig within chromosomal band 18q21 establishes physical linkage between BCL2 and plasminogen activator inhibitor type-2. Genomics 9, 219–228 (1991).

    CAS  PubMed  Google Scholar 

  65. Feinberg, A.P. & Vogelstein, B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity.Anal. Biochem. 132, 6–13 (1983).

    CAS  PubMed  Google Scholar 

  66. Chen, K.-S. et al. The human homologue of the Drosophila melanogasterflightless-I gene (fill) maps within the Smith-Magenis microdeletion critical region in 17p11.2. Am. J. Hum. Genet. 56, 175–182 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. van Tuinen, P., Rich, D.C., Summers, K.M. & Ledbetter, D.H. Regional mapping panel for human chromosome 17: application to neurofibromatosis type 1. Genomics 1, 374–381 (1987).

    CAS  PubMed  Google Scholar 

  68. Elder, F.F.B., Nichols, M.M., Hood, O.J. & Harrison, W.R. III.Unbalanced translocation (15;17)(q13;p13.3) with apparent Prader-Willi syndrome but without Miller-Dieker syndrome. Am. J. Med. Genet. 20, 519–524 (1985).

    CAS  PubMed  Google Scholar 

  69. Roa, B.B. et al. Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1 A. Nature Genet. 5, 189–194 (1993).

    CAS  PubMed  Google Scholar 

  70. Gyapay, G. et al. The 1993-94 Genethon human genetic linkage map. Nature Genet. 7, 246–249 (1994).

    CAS  PubMed  Google Scholar 

  71. Matise, T.C., Perlin, M. & Chakravarti, A. Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map. Nature Genet. 6, 384–390 (1994).

    CAS  PubMed  Google Scholar 

  72. Weissenbach, J. et al. A second-generation linkage map of the human genome. Nature 359, 794–801 (1992).

    CAS  PubMed  Google Scholar 

  73. Buetow, K.H. et al. Human genetic map; genome maps V: wall chart. Science 265, 2055–2070 (1994).

    CAS  PubMed  Google Scholar 

  74. Townsend-Nicholson, A., Baker, E., Sutherland, G.R. & Schofield, P.R. Localization of the adenosine A2b receptor subtype gene (ADORA2B) to chromosome 17p11.2-p12 by FISH and PCR screening of somatic cell hybrids. Genomics 25, 605–607 (1995).

    CAS  PubMed  Google Scholar 

  75. Hua, X., Wu, J., Goldstein, J.L., Brown, M.S. & Hobbs, H.H. Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBFl and SREBF2 to chromosomes 17p11.2 and 22q13. Genomics 25, 667–673 (1995).

    CAS  PubMed  Google Scholar 

  76. Campbell, H.D. et al. Genomic structure, evolution, and expression of human FLU, a gelsolin and leucine-rich-repeat family member: overlap with LLGL. Genomics 42, 46–54 (1997).

    CAS  PubMed  Google Scholar 

  77. Koyama, K. et al. The human homologue of the murine Llglh gene (LLGL) maps within the Smith-Magenis syndrome region in 17p11.2. Cytogenet. Cell Genet. 72, 78–82 (1996).

    CAS  PubMed  Google Scholar 

  78. Elsea, S.H. et al. Haploinsufficiency of cytosolic serine hydroxymethyltransferase in the Smith-Magenis syndrome. Am. J. Hum. Genet. 57, 1342–1350 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhao, Z. et al. The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients. Hum. Mol. Genet. 4, 589–597 (1995).

    CAS  PubMed  Google Scholar 

  80. Matsuda, Y. et al. Chromosome mapping of human (ZNF179), mouse, and rat genes for brain finger protein (bfp), a member of the RING finger family. Genomics 33, 325–327 (1996).

    CAS  PubMed  Google Scholar 

  81. Kimura, T. et al. The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2. Am. J. Med. Genet. 69, 320–324 (1997).

    CAS  PubMed  Google Scholar 

  82. Hiraoka, L.R., Hsu, L. & Hsieh, C.-L. Assignment of ALDH3 to human chromosome 17p11.2 and ALDH5 to human chromosome 9p13. Genomics 25, 323–325 (1995).

    CAS  PubMed  Google Scholar 

  83. De Laurenzi, V. et al. Sjögren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nature Genet. 12, 52–57 (1996).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Ken-Shiung Chen, Prasad Manian, Thearith Koeuth, Lorraine Potocki, Qi Zhao, A. Craig Chinault, Cheng Chi Lee & James R. Lupski

  2. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Prasad Manian

  3. Department of Pediatrics and Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Lorraine Potocki & James R. Lupski

  4. Human Genome Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    A. Craig Chinault, Cheng Chi Lee & James R. Lupski

Authors
  1. Ken-Shiung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prasad Manian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thearith Koeuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lorraine Potocki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Craig Chinault
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cheng Chi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James R. Lupski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James R. Lupski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, KS., Manian, P., Koeuth, T. et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet 17, 154–163 (1997). https://doi.org/10.1038/ng1097-154

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1097-154

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing