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Imprinted methylation profiles for proximal mouse Chromosomes 11 and 7 as revealed by methylation-sensitive representational difference analysis

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Abstract

Proximal mouse Chromosome (Chr) 11 shares regions of orthology with the candidate gene region for the imprinting growth disorder Silver-Russell syndrome (SRS) on human Chr 7p. It has previously been shown that mice with two maternal or two paternal copies (duplications, Dp) of proximal Chr 11 exhibit reciprocal growth phenotypes. Those with two paternal copies show fetal and placental overgrowth, while those with two maternal copies are growth retarded. The growth retardation observed in the latter is reminiscent of the intrauterine growth restriction (IUGR) observed in SRS patients with maternal uniparental disomy for Chr 7 (mUPD7). We have carried out a methylation-sensitive representational difference analysis (Me-RDA) screen to look for regions of differential methylation (DMRs) associated with imprinted genes. For these experiments, we have used mouse embryos with uniparental duplications of Chrs 11 and 7 proximal to the breakpoint of the reciprocal translocation T(7;11)40Ad. Two previously known imprinted loci associated with paternal allele hypomethylation were recovered on proximal mouse Chr 11, U2af1-rs1 and Meg1/Grb10. These two genes map 15 cM apart, so it seems likely that they are within separate imprinted domains that do not contain additional DMRs. The known imprinted gene Peg3, located on mouse proximal Chr 7, was also detected in our screen. The finding that Peg3 was differentially methylated in embryos with uniparental inheritance of proximal Chr 7 confirms that Peg3 is located proximal to the breakpoint of T40Ad in G-band 7A2. Because GRB10 has previously been reported to be a candidate gene for SRS, we analysed 22 patients for epimutations of the GRB10 differentially methylated region that could lead to the altered expression of this gene. No such mutations were found.

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Acknowledgements

We thank Susan Price for clinical assessment of the majority of SRS patients in the main cohort. We are also grateful to Lynn Jones and Emma Prescott for technical assistance with all aspects of the mouse genetic studies including identification and collection of embryos. The T(7;11)40Ad translocation stocks were a kind gift from Dr. Ilse-Dore Adler. This work was supported by funding from the MRC. P. Arnaud holds a Marie Curie Individual Fellowship from the European Community Programme in Human Potential (under contract number HPMF-CT-2001-01122), and G. Kelsey is a senior fellow of the MRC.

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Authors and Affiliations

  1. Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK

    David Monk, Philip Stanier & Gudrun E. Moore

  2. The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

    Rachel Smith, Philippe Arnaud & Gavin Kelsey

  3. Mammalian Genetics Unit, Medical Research Council, Harwell, Didcot, Oxfordshire, UK

    Colin V. Beechey & Jo Peters

  4. Institute of Child Health, University College London, London, UK

    Michael A. Preece

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  1. David Monk
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Correspondence to David Monk.

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Monk, D., Smith, R., Arnaud, P. et al. Imprinted methylation profiles for proximal mouse Chromosomes 11 and 7 as revealed by methylation-sensitive representational difference analysis . Mamm Genome 14, 805–816 (2003). https://doi.org/10.1007/s00335-003-2287-7

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