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The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice

Nature Genetics volume 28, pages 232–240 (2001)Cite this article

Abstract

In mice and humans, the locus encoding the gene for small nuclear ribonucleoprotein N (SNRPN/Snrpn), as well as other loci in the region are subject to genomic imprinting. The SNRPN promoter is embedded in a maternally methylated CpG island, is expressed only from the paternal chromosome and lies within an imprinting center that is required for switching to and/or maintenance of the paternal epigenotype. We show here that a 0.9-kb deletion of exon 1 of mouse Snrpn did not disrupt imprinting or elicit any obvious phenotype, although it did allow the detection of previously unknown upstream exons. In contrast, a larger, overlapping 4.8-kb deletion caused a partial or mosaic imprinting defect and perinatal lethality when paternally inherited.

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Figure 1: Generation of mice with nested deletions including Snrpn exon 1.
Figure 2: Characterization of mice inheriting the 0.9-kb deletion.
Figure 3: Identification of previously unknown upstream exons and alternatively spliced transcripts using 5′ RACE.
Figure 4: Characterization of mice inheriting the 4.8-kb deletion.

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References

  1. Nicholls, R.D., Saitoh, S. & Horsthemke, B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet. 14, 194–200 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Jiang, Y., Tsai, T.-F., Bressler, J. & Beaudet, A.L. Imprinting in Angelman and Prader- Willi syndromes. Curr. Opin. Genet. Dev. 8, 334–342 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Mann, M.R. & Bartolomei, M.S. Towards a molecular understanding of Prader-Willi and Angelman syndromes. Hum. Mol. Genet. 8, 1867–1873 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Schulze, A. et al. Exclusion of SNRPN as a major determinant of Prader-Willi syndrome by a translocation breakpoint. Nature Genet. 12, 452–454 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Sun, Y. et al. Breakage in the SNRPN locus in a balanced 46,XY,t(15;19) Prader-Willi syndrome patient. Hum. Mol. Genet. 5, 517–524 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Conroy, J.M. et al. Balanced translocation 46,XY,t(2;15)(q37.2;q11.2) associated with atypical Prader-Willi syndrome. Am. J. Hum. Genet. 61, 388–394 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kuslich, C.D., Kobori, J.A., Mohapatra, G., Gregorio-King, C. & Donlon, T. A. Prader- Willi syndrome is caused by disruption of the SNRPN gene. Am. J. Hum. Genet. 64, 70–76 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gray, T.A., Saitoh, S. & Nicholls, R D. An imprinted, mammalian bicistronic transcript encodes two independent proteins. Proc. Natl. Acad. Sci. USA 96, 5616–5621 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Blaydes, S.M., Elmore, M., Yang, T. & Brannan, C.I. Analysis of murine Snrpn and human SNRPN gene imprinting in transgenic mice. Mamm. Genome 10, 549–555 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Sutcliffe, J.S. et al. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nature Genet. 8, 52–58 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Glenn, C.C. et al. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am. J. Hum. Genet. 58, 335–346 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Shemer, R., Birger, Y., Riggs, A.D. & Razin, A. Structure of the imprinted mouse Snrpn gene and establishment of its parental-specific methylation pattern. Proc. Natl. Acad. Sci. USA 94, 10267–10272 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gabriel, J.M. et al. Structure and function correlations at the imprinted mouse Snrpn locus. Mamm. Genome 9, 788–793 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Buiting, K. et al. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nature Genet. 9, 395–400 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Dittrich, B. et al. Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nature Genet. 14, 163–170 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Saitoh, S. et al. Minimal definition of the imprinting center and fixation of a chromosome 15q11-q13 epigenotype by imprinting mutations. Proc. Natl. Acad. Sci. USA 93, 7811–7815 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Buiting, K., Lich, C., Cottrell, S., Barnicoat, A. & Horsthemke, B. A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum. Genet. 105, 665–666 (1999).

    CAS  PubMed  Google Scholar 

  18. Ohta, T. et al. Imprinting-mutation mechanisms in Prader-Willi syndrome. Am. J. Hum. Genet. 64, 397–413 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. Buiting, K. et al. Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: Implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am. J. Hum. Genet. 63, 170–180 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ferguson-Smith, A.C. Imprinting moves to the centre. Nature Genet. 14, 119–121 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Brannan, C.I. & Bartolomei, M.S. Mechanisms of genomic imprinting. Curr. Opin. Genet. Dev. 9, 164–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Shemer, R. et al. The imprinting box of the Prader-Willi/Angelman syndrome domain. Nature Genet. 26, 440–443 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Tilghman, S.M., Caspary, T. & Ingram, R.S. Competitive edge at the imprinted Prader-Willi/Angelman region? Nature Genet. 18, 206–208 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Bielinska, B. et al. De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch. Nature Genet. 25, 74–78 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Yang, T. et al. A mouse model for Prader-Willi syndrome imprinting-centre mutations. Nature Genet. 19, 25–31 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Huq, A.H.M.M. et al. Sequencing and functional analysis of the SNRPN promoter: In vitro methylation abolishes promoter activity. Genome Res. 7, 642–648 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mutirangura, A. et al. A complete yeast artificial chromosome (YAC) contig of the Prader-Willi/Angelman syndrome (PWS/AS) region and refined localization of the SNRPN gene. Genomics 18, 546 (1993).

  29. Watrin, F. et al. The mouse necdin gene is expressed from the paternal allele only and lies in the 7C region of the mouse chromosome 7, a region of conserved synteny to the human Prader-Willi syndrome region. Eur. J. Hum. Genet. 5, 324–332 (1997).

    CAS  PubMed  Google Scholar 

  30. Tsai, T.F., Jiang, Y.H., Bressler, J., Armstrong, D. & Beaudet, A.L. Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader-Willi syndrome. Hum. Mol. Genet. 8, 1357–1364 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Farber, C., Dittrich, B., Buiting, K. & Horsthemke, B. The chromosome 15 imprinting centre (IC) region has undergone multiple duplication events and contains an upstream exon of SNRPN that is deleted in all Angelman syndrome patients with an IC microdeletion. Hum. Mol. Genet. 8, 337–343 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Gillessen-Kaesbach, G. et al. A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by an imprinting defect. Eur. J. Hum. Genet. 7, 638–644 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Wolff, G.L., Kodell, R.L., Moore, S.R. & Cooney, C.A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12, 949–957 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. Gabriel, J.M. et al. A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and Angelman syndromes. Proc. Natl. Acad. Sci. USA 96, 9258–9263 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. El Maarri, O. et al. Maternal methylation imprints on human chromosome 15 are established during or after fertilization. Nature Genet. 27, 341–344 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. de Los, S.T., Schweizer, J., Rees, C.A. & Francke, U. Small evolutionarily conserved RNA, resembling C/D box small nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which is highly expressed in brain. Am. J. Hum. Genet. 67, 1067–1082 (2000).

    Article  Google Scholar 

  38. Cavaille, J. et al. From the Cover: Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc. Natl. Acad. Sci. USA 97, 14311–14316 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tsai, T.-F., Armstrong, D. & Beaudet, A.L. Necdin deficient mice do not show lethality or the obesity and infertility of Prader-Willi syndrome. Nature Genet. 22, 15–16 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Gerard, M., Hernandez, L., Wevrick, R. & Stewart, C.L. Disruption of the mouse necdin gene results in early post-natal lethality. Nature Genet. 23, 199–202 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Muscatelli, F. et al. Disruption of the mouse necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum. Mol. Genet. 9, 3101–3110 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Simpson, E.M. et al. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nature Genet. 16, 19–27 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Southern, E.M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J. Mol. Biol. 98, 503 (1975).

    Article  CAS  PubMed  Google Scholar 

  44. Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular Cloning. A Laboratory Manual (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Wevrick, R. & Francke, U. An imprinted mouse transcript homologous to the human imprinted in Prader-Willi syndrome (IPW) gene. Hum. Mol. Genet. 6, 325–332 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. MacDonald, H.R. & Wevrick, R. The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum. Mol. Genet. 6, 1873–1878 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Abuin, A. & Bradley, A. Recycling selectable markers in mouse embryonic stem cells. Mol. Cell. Biol. 16, 1851–1856 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ramirez-Solis, R., Davis, A.C. & Bradley, A. Gene targeting in embryonic stem cells. Methods Enzymol. 225, 855 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Sierra for technical assistance and Y.-h. Jiang for discussions. We thank B. Horsthemke for communications and sharing information before publication. J.B. thanks T-F. T., without whose support and contributions, this work would not have been possible. This work was supported by US National Institutes of Health grant HD-37283 and Taiwan NSC89-2320-B-D10-044.

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Authors and Affiliations

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

    Jan Bressler, Ting-Fen Tsai, Mei-Yi Wu, Maricela A. Ramirez & Arthur L. Beaudet

  2. Department of Pathology, Baylor College of Medicine, Houston, Texas, USA

    Dawna Armstrong

  3. Department of Life Sciences, National Yang- Ming University, Taipei, Taiwan

    Ting-Fen Tsai & Mei-Yi Wu

  4. Institute of Genetics, National Yang- Ming University, Taipei, Taiwan

    Shih-Feng Tsai

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Correspondence to Arthur L. Beaudet.

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Bressler, J., Tsai, TF., Wu, MY. et al. The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice. Nat Genet 28, 232–240 (2001). https://doi.org/10.1038/90067

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