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Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1

Nature Genetics volume 32, pages 426–431 (2002)Cite this article

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Abstract

Genomic imprinting is an epigenetic modification that results in expression from only one of the two parental copies of a gene. Differences in methylation between the two parental chromosomes are often observed at or near imprinted genes. Beckwith–Wiedemann syndrome (BWS), which predisposes to cancer and excessive growth, results from a disruption of imprinted gene expression in chromosome band 11p15.5. One third of individuals with BWS lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene1,2,3, and it has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS1,2. Here we show that paternal inheritance of a deletiion of KvDMR1 results in the de-repression in cis of six genes, including Cdkn1c, which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20–25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings support the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS.

NOTE: In the AOP version of this article, the fourth sentence of the abstract contained a mistake. The sentence should have read "Here we show that paternal inheritance of a deletion of KvDMR1 results in...". This has been corrected in the HTML and PDF versions, and the article will appear correctly in a forthcoming print issue.

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Figure 1: Physical map of the imprinted domain in mouse distal chromosome 7, targeting strategy for deletion of KvDMR1 and effect of deletion on Kcnq1ot1.
Figure 2: Paternal transmission of the KvDMR1 deletion results in loss of imprinting of maternal-specific genes in cis but has no effect on the paternally expressed Igf2 gene.
Figure 3: Growth deficiency in mice with a paternally inherited deletion of KvDMR1.
Figure 4: Complete de-repression of the paternal alleles of maternal-specific genes in mice inheriting a KvDMR1 deletion from their fathers.
Figure 5: Function of KvDMR1 and its relationship to BWS.

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Change history

  • 03 October 2002

    This was incorrect in AOP version. Corrected the fourth sentence as per note.

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Acknowledgements

We thank the Department of Laboratory Animal Research, Gene Targeting and Transgenics and Biopolymer core facilities at Roswell Park Cancer Institute for help; A. Nagy for the loxP-flanked neomycin-resistance cassette; R. Elliott for PWK mice; and W. Reik for the SD7 mice. This work was supported by grants from the Roswell Park Alliance Foundation and US National Cancer Institute/National Institutes of Health to M.J.H.

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Authors and Affiliations

  1. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, 14263, New York, USA

    Galina V. Fitzpatrick & Michael J. Higgins

  2. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, 14263, New York, USA

    Paul D. Soloway

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Correspondence to Michael J. Higgins.

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Fitzpatrick, G., Soloway, P. & Higgins, M. Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1. Nat Genet 32, 426–431 (2002). https://doi.org/10.1038/ng988

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