Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes1,2,3,4,5. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole6, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment.
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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).
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).
Reik, W. et al. Imprinting mutations in the Beckwith-Wiedemann syndrome suggested by altered imprinting pattern in the IGF2-H19 domain. Hum. Mol. Genet. 4, 2379–2385 (1995).
Gardner, R. J. et al. An imprinted locus associated with transient neonatal diabetes mellitus. Hum. Mol. Genet. 9, 589–596 (2000).
Liu, J. et al. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J. Clin. Invest. 106, 1167–1174 (2000).
Kajii, T. & Ohama, K. Androgenetic origin of hydatidiform mole. Nature 268, 633–634 (1977).
Moglabey, Y. B. et al. Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum. Mol. Genet. 8, 667–671 (1999).
Helwani, M. N. et al. A familial case of recurrent hydatidiform molar pregnancies with biparental genomic contribution. Hum. Genet. 105, 112–115 (1999).
Fisher, R. A., Khatoon, R., Paradinas, F. J., Roberts, A. P. & Newlands, E. S. Repetitive complete hydatidiform mole can be biparental in origin and either male or female. Hum. Reprod. 15, 594–598 (2000).
Clark, S. J., Harrison, J., Paul, C. L. & Frommer, M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 22, 2990–2997 (1994).
Kerjean, A. et al. Establishment of the paternal methylation imprint of the human H19 and MEST/PEG1 genes during spermatogenesis. Hum. Mol. Genet. 9, 2183–2187 (2000).
Lee, M. P. et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc. Natl Acad. Sci. USA 96, 5203–5208 (1999).
Ohta, T. et al. Imprinting-mutation mechanisms in Prader-Willi syndrome. Am. J. Hum. Genet. 64, 397–413 (1999).
Engemann, S. et al. Sequence and functional comparison in the Beckwith-Wiedemann region: implications for a novel imprinting centre and extended imprinting. Hum. Mol. Genet. 9, 2691–2706 (2000).
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).
El-Maarri, O. et al. Maternal methylation imprints on human chromosome 15 are established during or after fertilization. Nature Genet. 27, 341–344 (2001).
Kaneko-Ishino, T. et al. Peg1/Mest imprinted gene on chromosome 6 identified by cDNA subtraction hybridization. Nature Genet. 11, 52–59 (1995).
Murphy, S. K., Wylie, A. A. & Jirtle, R. L. Imprinting of PEG3, the human homologue of a mouse gene involved in nurturing behavior. Genomics 71, 110–117 (2001).
Hayward, B. E. et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc. Natl Acad. Sci. USA 95, 10038–10043 (1998).
Hayward, B. E., Moran, V., Strain, L. & Bonthron, D. T. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc. Natl Acad. Sci. USA 95, 15475–15480 (1998).
Hayward, B. E. & Bonthron, D. T. An imprinted antisense transcript at the human GNAS1 locus. Hum. Mol. Genet. 9, 835–841 (2000).
Liu, J., Yu, S., Litman, D., Chen, W. & Weinstein, L. S. Identification of a methylation imprint mark within the mouse Gnas locus. Mol. Cell Biol. 20, 5808–5817 (2000).
Smilinich, N. J. et al. A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proc. Natl Acad. Sci. USA 96, 8064–8069 (1999).
Kamiya, M. et al. The cell cycle control gene ZAC/PLAGL1 is imprinted—a strong candidate gene for transient neonatal diabetes. Hum. Mol. Genet. 9, 453–460 (2000).
Reik, W. & Walter, J. Evolution of imprinting mechanisms: the battle of the sexes begins in the zygote. Nature Genet. 27, 255–256 (2001).
Bourc’his, D., Xu, G.-L., Lin, C.-S., Bollman, B. & Bestor, T. H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536–2539 (2001); advance online publication, 29 November 2001 (DOI 10,1126/Science.1065848).
Strain, L., Warner, J. P., Johnston, T. & Bonthron, D. T. A human parthenogenetic chimaera. Nature Genet. 11, 164–169 (1995).
We thank R. Fisher for supplying androgenetic CHM DNAs, and G. Taylor for Prader–Willi and chorionic villus sample DNA samples. This work was supported by the Wellcome Trust.
The authors declare that they have no competing financial interests
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Judson, H., Hayward, B., Sheridan, E. et al. A global disorder of imprinting in the human female germ line. Nature 416, 539–542 (2002). https://doi.org/10.1038/416539a
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