Inherited microdeletions in the Angelman and Prader–Willi syndromes define an imprinting centre on human chromosome 15

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  • A Correction to this article was published on 01 June 1995

Abstract

A subset of patients with Angelman and Prader–Willi syndrome have apparently normal chromosomes of biparental origin, but abnormal DMA methylation at several loci within chromosome 15q11–13, and probably have a defect in imprinting. Using probes from a newly established 160–kb contig including D15S63 (PW71) and SNRPN, we have identified inherited microdeletions in two AS families and three PWS families. The deletions probably affect a single genetic element that we term the 15q11–13 imprinting centre (IC). In our model, the IC regulates the chromatin structure, DMA methylation and gene expression in cis throughout 15q11–13. Mutations of the imprinting centre can be transmitted silently through the germline of one sex, but appear to block the resetting of the imprint in the germline of the opposite sex.

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References

  1. 1

    Nicholls, R.D. Genomic imprinting and candidate genes in the Prader-Willi and Angelman syndromes. Curr. Opin. Genet. Dev. 3, 445–456 (1993).

  2. 2

    Özcelik, 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).

  3. 3

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

  4. 4

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

  5. 5

    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).

  6. 6

    Wevrick, R., Kerns, J.A. & Francke, U. Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. Hum. molec. Genet. 3, 1877–1882 (1994).

  7. 7

    Razin, A. & Cedar, H. DNA methylation and genomic Imprinting. Cell 77, 473–476 (1994).

  8. 8

    Kitsberg, D. et al. Allele-specific replication timing of imprinted gene regions. Nature 364, 459–463 (1993).

  9. 9

    Knoll, J.H.G., Cheng, S.-D. & Lalande, M. Allele specificity of DNA replication timing in the Angelman/Prader-Willi syndrome imprinted chromosomal region. Nature Genet. 6, 41–46 (1994).

  10. 10

    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).

  11. 11

    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).

  12. 12

    Dittrich, B., Buiting, K., Gross, S. & Horsthemke, B. Characterization of a methylation imprint in the Prader-Willi syndrome region. Hum. molec. Genet. 2, 1995–1999 (1993).

  13. 13

    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).

  14. 14

    Gillessen-Kaesbach, G., Gross, S., Kaya Westerloh, S., Passarge, E. & Horsthemke, B. DNA methylation based testing of 450 patients suspected of having Prader-Willi syndrome. J. med. Genet. (in the press).

  15. 15

    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).

  16. 16

    Suiting, K. et al. Detection of aberrant DNA methylation in unique Prader-Willi syndrome patients and its diagnostic implications. Hum. molec. Genet. 3, 893–695 (1994). (Corrigendum Hum. molec. Genet. 3, 2092 (1994)).

  17. 17

    Mutirangura, A. et al. A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11–13) and refined localization of the SNRPN gene. Genomics 18, 546–552 (1993).

  18. 18

    Malcolm, S. & Donlon, T.A. Report of the second international workshop on human chromosome 15 mapping 1994. Cytogenet. Cell. Genet. 67, 1–36 (1994).

  19. 19

    Buxton, J.L. et al. Angelman syndrome associated with a maternal 15q11–13 deletion of less than 200 kb. Hum. molec. Genet. 3, 1409–141 (1994).

  20. 20

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

  21. 21

    Horsthemke, B., Dittrtch, B. & Buiting, K. Parent-of-origin specific DNA methylation and imprinting mutations on human chromosome 15. in Proceedings of the Nobel Conference on Parental Imprinting (eds Ohlson, R., Hall, K. & Ritzén, M.) (Cambridge University Press, in the press).

  22. 22

    Dittrich, B., Buiting, K., Gross, S., Horsthemke, B. An insertion/deletion polymorphism at the D15S63 locus in the critical Prader-Willi syndrome region in 15q11–13. Hum. Genet 94, 583–584 (1994).

  23. 23

    Gabriel, J. et al. A common Insertion/deletion polymorphism in the Prader-Willi syndrome minimal critical region. Hum. molec. Genet. 3, 1912 (1994).

  24. 24

    Schmauss, C., Brines, M.L. & Lerner, 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).

  25. 25

    Vanin, E.F., Henthorn, P.S., Kioussis, D., Grosveld, F. & Smithies, O. Unexpected relationships between four large deletions in the human β-globin gene cluster. Cell 35, 701–709 (1983).

  26. 26

    Nicholls, R.D., Fischel-Ghodsian, N. & Higgs, D.R. Recombination at the human a-globin gene cluster: sequence features and topological constraints. Cell 49, 369–378 (1987).

  27. 27

    Karpen, G.H. Position-effect variegation and the new biology of heterochromatin. Curr. Opin. Genet. Dev. 4, 281–291 (1994).

  28. 28

    Barlow, D.P. Methylation and imprinting: from host defense to gene regulation? Science 260, 309–310 (1993).

  29. 29

    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 (1994).

  30. 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).

  31. 31

    Lubinsky, M. et al. Familial Prader-Willi syndrome with apparently normal chromosomes. Am. J. med. Genet. 28, 37–43 (1987).

  32. 32

    Silverman, G.A., Ye, R.D., Pollock, K.M., Sadler, J.E. & Korsmeyer, S.J. Use of yeast artificial chromosome clones for mapping and walking within human chromosome segment 18q21.3. Proc. natn. Acad. Sci. U.S.A. 86, 7485–7489 (1989).

  33. 33

    Lengauer, C., Green, E.D. & Cremer, T. Fluorescence in situ hybridization of YAC clones after Alu-PCR amplification. Genomics 13, 826–828 (1982).

  34. 34

    Bulting, K. .et al. Molecular definition of the Prader-Willi syndrome chromosome region and orientation of the SNRPN gene. Hum. molec. Genet. 2, 1991–1994 (1993).

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Buiting, K., Saitoh, S., Gross, S. et al. Inherited microdeletions in the Angelman and Prader–Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 9, 395–400 (1995) doi:10.1038/ng0495-395

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