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Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57

Abstract

We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57, which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.

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Figure 1: Sequence analysis of mutations in ZFP57.

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Acknowledgements

We thank E. Cross, C. Forristal, F. Houghton, C. Mattocks, A. Skinner and O. Wood for expert experimental assistance, N. Morton for calculating the degree of consanguinity of individuals in this study, the individuals with TND and their families for participation in the study and clinicians for their collaboration in this work. Funding for this study was from Diabetes UK (BDA:RD04/0002932 to D.J.G.M. and BDA:RD06/0003185 to J.L.A.C.).

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Contributions

D.J.G.M., J.L.A.C., S.M.M., H.E.W. and D.O.R. designed and performed genetic and epigenetic tests, and D.J.G.M. co-ordinated the molecular part of the study. C.L.A., S.E.B., P.D., H.V.F., J.A.G., A.P.H., J.M.D.H., O.K., A.F.M., E.O., J.S., S.E., A.T.H. and I.K.T. were involved in clinical characterization and referral of individuals with TND and the clinical study was coordinated by I.K.T.

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Correspondence to Deborah J G Mackay.

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Supplementary Methods, Supplementary Figures 1 and 2, Supplementary Tables 1–3 (PDF 926 kb)

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Mackay, D., Callaway, J., Marks, S. et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 40, 949–951 (2008). https://doi.org/10.1038/ng.187

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