A global disorder of imprinting in the human female germ line

Abstract

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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Figure 1: Bisulphite sequencing of DMRs in imprinted genes.
Figure 2: Bisulphite analysis of GNAS1.

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Acknowledgements

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.

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Correspondence to David T. Bonthron.

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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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