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:

Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region

Nature Genetics volume 8, pages 52–58 (1994)Cite this article

Abstract

To determine the molecular basis of Prader-Willi syndrome (PWS) and Angelman syndrome (AS), we have isolated new transcripts from chromosome 15q11–q13. Two novel transcripts located within 300 kilobases telomeric to the small nuclear ribonucleoprotein-associated polypeptide N gene (SNRPN) were paternally expressed in cultured cells, along with SNRPN, defining a large imprinted transcriptional domain. In three PWS patients (two sibs), small deletions remove a differentially methylated CpG island containing a newly described 5′ exon α of SNRPN, and cause loss of expression for the three imprinted transcripts and altered methylation over hundreds of kilobases. The smallest PWS deletion is familial and asymptomatic with maternal transmission. Our data imply the presence of a paternal imprinting control region near exon α.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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. Ledbetter, D.H. et al. Deletions of chromosome 15 as a cause of the Prader–Willi syndrome. New Engl. J. Med. 304, 325–329 (1981).

    Article  CAS  PubMed  Google Scholar 

  2. Knoll, J.H.M. et al. Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am. J. med. Genet. 32, 285–290 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Nicholls, R.D., Knoll, J.H.M., Butler, M.G., Karam, S. & Lalande, M. Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome. Nature 342, 281–285 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Malcolm, S. et al. Uniparental paternal disomy in Angelman's syndrome. Lancet 337, 694–697 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Holm, V.A. et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 91, 398–402 (1993).

    CAS  PubMed  Google Scholar 

  6. Robinson, W.P. et al. Molecular, cytogenetic, and clinical investigations of Prader-Willi syndrome patients. Am. J. hum. Genet. 49, 1219–1234 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mutirangura, A. et al. A complete YAC contig of the Prader–Willi/Angelman chromosome region (15q11–q13) and refined localization of the SNRPN gene. Genomics 18, 546–552 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Reis, A. et al. Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader–Willi syndromes. Am. J. hum. Genet. 54, 741–747 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Mascari, M.J. et al. The frequency of uniparental disomy in Prader–Willi syndrome. Implications for molecular diagnosis. New Engl. J. Med. 326, 1599–1607 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Meijers-Heijboer, E.J. et al. Linkage analysis with chromosome 15q11–13 markers shows genomic imprinting in familial Angelman syndrome. J. med. Genet. 29, 853–857 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Clayton-Smith, J. et al. Further evidence for dominant inheritance at the chromosome 15q11–13 locus in familial Angelman syndrome. Am J. med. Genet. 44, 256–260 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Wagstaff, J. et al. Maternal but not paternal transmission of 15q11–13-linked nondeletion Angelman syndrome leads to phenotypic expression. Nature Genet. 1, 291–294 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Kuwano, A. et al. Molecular dissection of the Prader-Willi/Angelman syndrome region (15q11–13) by YAC cloning and FISH analysis. Hum. molec. Genet. 1, 417–425 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Reis, A. et al. Exclusion of the GABA-receptor b3 subunit gene as the Angelman's syndrome gene. Lancet 341, 122–123 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Hamabe, J. et al. DNA deletion and its parental origin in Angelman syndrome patients. Am. J. med. Genet. 41, 64–68 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Saitoh, S. et al. Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABAA receptor b3 subunit gene. Lancet 339, 366–367 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Özçelik, T. et al. Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region. Nature Genet. 2, 265–269 (1992).

    Article  PubMed  Google Scholar 

  18. Leff, S.E. et al. Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader-Willi syndrome region. Nature Genet. 2, 259–264 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Cattanach, B.M. et al. A candidate mouse model for Prader-Willi syndrome which shows an absence of Snrpn expression. Nature Genet. 2, 270–274 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Nakao, M. et al. Imprinting analysis of three genes in the Prader–Willi/ Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum. molec. Genet. 3, 309–315 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Glenn, C.C., Porter, K.A., Jong, M.T.C., Nicholls, R.D. & Driscoll, D.J. Functional imprinting and epigenetic modification of the human SNRPN gene. Hum. molec. Genet. 2, 2001–2005 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Reed, M.L. & Leff, S.E. Maternal imprinting of human SNRPN, a gene deleted in the Prader-Willi syndrome. Nature Genet. 6, 163–167 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Dittrich, B. et al. Molecular diagnosis of the Prader–Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11–13. Hum. Genet. 90, 313–315 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Driscoll, D.J. et al. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader–Willi syndromes. Genomics 13, 917–924 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Glenn, C.C. et al. Modification of 15q11–q13 DNA methylation imprints in unique Angelman and Prader-Willi patients. Hum. molec. Genet. 2, 1377–1382 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Nicholls, R.D. New insights reveal complex mechanisms involved in genomic imprinting. Am. J. hum. Genet. 54, 733–740 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Huibregtse, J.M., Scheffner, M. & Howley, P.M. Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Molec. cell. Biol. 13, 775–784 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sutcliffe, J.S., Zhang, F., Caskey, C.T., Nelson, D.L. & Warren, S.T. PCR amplification and analysis of yeast artificial chromosomes. Genomics 13, 1303–1306 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. McAllister, G., Amara, S.G. & Lemer, M.R. Tissue-specific expression and cDNA cloning of small nuclear ribonucleoprotein-associated polypeptide N. Proc. natn. Acad. Sci. U.S.A. 85, 5296–5300 (1988).

    Article  CAS  Google Scholar 

  30. Örstavik, K.H. et al. Prader–Willi syndrome in a brother and sister without cytogenetic or detectable molecular genetic abnormality at chromosome 15q11q13. Am. J. med. Genet. 44, 534–538 (1992).

    Article  PubMed  Google Scholar 

  31. Pettigrew, A.L., Gollin, S.M., Greenberg, F., Riccardi, V.M. & Ledbetter, D.H. Duplication of proximal 15q as a cause of Prader–Willi syndrome. Am. J. med. Genet. 28, 791–802 (1987).

    Article  CAS  PubMed  Google Scholar 

  32. Schmauss, C., Brines, M.L. & Lemer, M.R. The gene encoding the small nuclear ribonucleoprotein-associated protein N is expressed at high levels in neurons. J. biol. Chem. 267, 8521–8529 (1992).

    CAS  PubMed  Google Scholar 

  33. Schmauss, C., McAllister, G., Ohosone, Y., Hardin, J.A. & Lerner, M.R. A comparison of snRNP-associated Sm-autoantigens: human N, rat N and human B/B′. Nucl. Acids Res. 17, 1733–1743 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rokeach, L.A., Jannatipour, M., Haselby, J.A. & Hoch, S.O. Primary structure of a human small nuclear ribonucleoprotein polypeptide as deduced by cDNA analysis. J. biol. Chem. 264, 5024–5030 (1989).

    CAS  PubMed  Google Scholar 

  35. Brown, C.J. et al. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527–542 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Zemel, S., Bartolomei, M.S. & Tilghman, S.M. Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2. Nature Genet. 2, 61–65 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Bartolomei, M.S. & Tilghman, S.M. Parental imprinting of mouse chromosome 7. Sem. Devi. Biol. 3, 107–117 (1992).

    Google Scholar 

  38. Bartolomei, M.S., Webber, A.L., Brunkow, M.E. & Tilghman, S.M. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev. 7, 1663–1673 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Li, E., Beard, C. & Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Southern, E.M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J. molec. Biol. 98, 503–517 (1975).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Sealy, P.G., Whittaker, P.A. & Southern, E.M. Removal of repeated sequences from hybridization probes. Nucl. Acids Res. 13, 1905–1922 (1985).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. Anand, R., Villasante, A. & Tyler-Smith, C. Construction of yeast artificial chromosome libraries with large inserts using fractionation by pulsed-field gel electrophoresis. Nucl. Acids Res. 17, 3425–3433 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Smith, C.L., Klco, S.R. & Cantor, C.R. in Genome Analysis: A Practical Approach (ed. Davies, K.E. ) 41–72 (IRL Press, Oxford, 1988).

    Google Scholar 

  46. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chioroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  PubMed  Google Scholar 

  47. Kuwano, A., Ledbetter, S.A., Dobyns, W.B., Emanuel, B.S. & Ledbetter, D.H. Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. Am. J. hum. Genet. 49, 707–714 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zoghbi, H.Y. et al. Assignment of autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6, using multilocus linkage analysis. Am. J. hum. Genet. 44, 255–263 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    James S. Sutcliffe, Mitsuyoshi Nakao & Arthur L. Beaudet

  2. National Center for Human Genome Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland, 20892, USA

    Susan Christian & David H. Ledbetter

  3. Department of Medical Genetics, Uttevål University Hospital, Oslo, Norway

    Karen H. Örstavik

  4. Danish Center for Human Genome Research, The John F. Kennedy Institute, Glostrup, DK-2600, Denmark

    Niels Tommerup

Authors
  1. James S. Sutcliffe
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Mitsuyoshi Nakao
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Susan Christian
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Karen H. Örstavik
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Niels Tommerup
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. David H. Ledbetter
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Arthur L. Beaudet
    View author publications

    You can also search for this author inPubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sutcliffe, J., Nakao, M., Christian, S. et al. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet 8, 52–58 (1994). https://doi.org/10.1038/ng0994-52

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0994-52

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