Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes

Nature Genetics volume 40, pages 237–242 (2008)Cite this article

Abstract

Human chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1 and maternally expressed genes (MEGs) such as MEG3 (also known as GTL2), RTL1as (RTL1 antisense) and MEG8 (refs. 1,2), together with the intergenic differentially methylated region (IG-DMR) and the MEG3-DMR3,4,5. Consistent with this, paternal and maternal uniparental disomy for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes6,7. We studied eight individuals (cases 1–8) with a upd(14)pat-like phenotype and three individuals (cases 9–11) with a upd(14)mat-like phenotype in the absence of upd(14) and identified various deletions and epimutations affecting the imprinted region. The results, together with recent mouse data4,8,9,10, imply that the IG-DMR has an important cis-acting regulatory function on the maternally inherited chromosome and that excessive RTL1 expression and decreased DLK1 and RTL1 expression are relevant to upd(14)pat-like and upd(14)mat-like phenotypes, respectively.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The pedigrees of two families.
Figure 2: The regional physical map of the human chromosome 14q32.2 imprinted region and the four deletion intervals identified in this study.
Figure 3: Methylation patterns of the IG-DMR (CG4 and CG6) (those of the MEG3-DMR (CG7) are shown in Supplementary Fig. 2b).
Figure 4: FISH results for the IG-DMR.
Figure 5: Examinations of placental samples.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Cavaille, J., Seitz, H., Paulsen, M., Ferguson-Smith, A.C. & Bachellerie, J.P. Identification of tandemly-repeated C/D snoRNA genes at the imprinted human 14q32 domain reminiscent of those at the Prader-Willi/Angelman syndrome region. Hum. Mol. Genet. 11, 1527–1538 (2002).

    Article  CAS  Google Scholar 

  2. Charlier, C. et al. Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8. Genome Res. 11, 850–862 (2001).

    Article  CAS  Google Scholar 

  3. Paulsen, M. et al. Comparative sequence analysis of the imprinted Dlk1-Gtl2 locus in three mammalian species reveals highly conserved genomic elements and refines comparison with the Igf2–H19 region. Genome Res. 11, 2085–2094 (2001).

    Article  CAS  Google Scholar 

  4. Lin, S.P. et al. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat. Genet. 35, 97–102 (2003).

    Article  CAS  Google Scholar 

  5. Murphy, S.K. et al. Epigenetic detection of human chromosome 14 uniparental disomy. Hum. Mutat. 22, 92–97 (2003).

    Article  CAS  Google Scholar 

  6. Kagami, M. et al. Segmental and full paternal isodisomy for chromosome 14 in three patients: narrowing the critical region and implication for the clinical features. Am. J. Med. Genet. A. 138, 127–132 (2005).

    Article  Google Scholar 

  7. Kotzot, D. Maternal uniparental disomy 14 dissection of the phenotype with respect to rare autosomal recessively inherited traits, trisomy mosaicism, and genomic imprinting. Ann. Genet. 47, 251–260 (2004).

    Article  Google Scholar 

  8. Sekita, Y. et al. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat. Genet. advance online publication, 10.1038/ng.2007.51 (6 January 2008).

  9. Seitz, H. et al. Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nat. Genet. 34, 261–262 (2003).

    Article  CAS  Google Scholar 

  10. Davis, E. et al. RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus. Curr. Biol. 15, 743–749 (2005).

    Article  CAS  Google Scholar 

  11. Takahashi, I., Takahashi, T., Utsunomiya, M., Takada, G. & Koizumi, A. Long-acting gonadotropin-releasing hormone analogue treatment for central precocious puberty in maternal uniparental disomy chromosome 14. Tohoku J. Exp. Med. 207, 333–338 (2005).

    Article  Google Scholar 

  12. Rosa, A.L. et al. Allele-specific methylation of a functional CTCF binding site upstream of MEG3 in the human imprinted domain of 14q32. Chromosome Res. 13, 809–818 (2005).

    Article  CAS  Google Scholar 

  13. Kosaki, K. et al. Diagnosis of maternal uniparental disomy of chromosome 7 with a methylation specific PCR assay. J. Med. Genet. 37, E19 (2000).

    Article  CAS  Google Scholar 

  14. Gicquel, C. et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat. Genet. 37, 1003–1007 (2005).

    Article  CAS  Google Scholar 

  15. Kubota, T. et al. Methylation-specific PCR simplifies imprinting analysis. Nat. Genet. 16, 16–17 (1997).

    Article  CAS  Google Scholar 

  16. Kaneko-Ishino, T., Kohda, T. & Ishino, F. The regulation and biological significance of genomic imprinting in mammals. J. Biochem. 133, 699–711 (2003).

    Article  CAS  Google Scholar 

  17. Coan, P.M., Burton, G.J. & Ferguson-Smith, A.C. Imprinted genes in the placenta—a review. Placenta 26 (Suppl. A), S10–S20 (2005).

    Article  Google Scholar 

  18. Kaneko-Ishino, T., Kohda, T., Ono, R. & Ishino, F. Complementation hypothesis: the necessity of a monoallelic gene expression mechanism in mammalian development. Cytogenet. Genome Res. 113, 24–30 (2006).

    Article  CAS  Google Scholar 

  19. Takada, S. et al. Epigenetic analysis of the Dlk1-Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2–H19. Hum. Mol. Genet. 11, 77–86 (2002).

    Article  CAS  Google Scholar 

  20. Georgiades, P., Watkins, M., Surani, M.A. & Ferguson-Smith, A.C. Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12. Development 127, 4719–4728 (2000).

    CAS  PubMed  Google Scholar 

  21. Lin, S.P. et al. Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region. Development 134, 417–426 (2007).

    Article  CAS  Google Scholar 

  22. Moon, Y.S. et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol. Cell. Biol. 22, 5585–5592 (2002).

    Article  CAS  Google Scholar 

  23. Temple, I.K. et al. Isolated imprinting mutation of the DLK1/GTL2 locus associated with a clinical presentation of maternal uniparental disomy of chromosome 14. J. Med. Genet. 44, 637–640 (2007) published online 29 June 2007.

    Article  CAS  Google Scholar 

  24. Hernandez, A., Martinez, M.E., Fiering, S., Galton, V.A. & St Germain, D.L. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J. Clin. Invest. 116, 476–484 (2006).

    Article  CAS  Google Scholar 

  25. Tsai, C.E. et al. Genomic imprinting contributes to thyroid hormone metabolism in the mouse embryo. Curr. Biol. 12, 1221–1226 (2002).

    Article  CAS  Google Scholar 

  26. Sekita, Y. et al. Aberrant regulation of imprinted gene expression in Gtl2lacZ mice. Cytogenet. Genome Res. 113, 223–229 (2006).

    Article  CAS  Google Scholar 

  27. Lewis, A. et al. Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nat. Genet. 36, 1291–1295 (2004).

    Article  CAS  Google Scholar 

  28. Umlauf, D. et al. Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nat. Genet. 36, 1296–1300 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank all the affected individuals and their family members who participated in this study. This work was supported by Grants for Child Health and Development (17C-2) and for Research on Children and Families (H18-005) from the Ministry of Health, Labor, and Welfare, and by Grants-in-Aid for Scientific Research (priority areas: 16086215 and 1508023; category B: 19390290) from the Ministry of Education, Culture, Sports, Science and Technology.

Author information

Author notes

  1. Masayo Kagami and Yoichi Sekita: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan

    Masayo Kagami, Fumiko Kato, Michiyo Okada & Tsutomu Ogata

  2. Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan

    Yoichi Sekita, Masahito Irie & Fumitoshi Ishino

  3. Department of Radiology, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo, 204-8567, Japan

    Gen Nishimura

  4. Mitsubishi Chemical Medience Corporation, Tokyo, 174-8555, Japan

    Shunji Yamamori

  5. Division of Pathology, Saitama Children's Medical Center, Saitama, 339-8551, Japan

    Hiroshi Kishimoto

  6. Division of Pathology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, 594-1101, Japan

    Masahiro Nakayama

  7. Divison of Pathology, Kanagawa Children's Medical Center, Yokohama, 232-8555, Japan

    Yukichi Tanaka

  8. Division of Pathology, National Center for Child Health and Development, Tokyo, 157-8535, Japan

    Kentarou Matsuoka

  9. Department of Pediatrics, Akita University School of Medicine, Akita, 010-8543, Japan

    Tsutomu Takahashi

  10. Department of Neonatology, Chiba Kaihin Municipal Hospital, Chiba, 261-0012, Japan

    Mika Noguchi

  11. Department of Pediatrics, Tokyo Dental College Ichikawa General Hospital, Ichikawa, 272-8513, Japan

    Yoko Tanaka

  12. Department of Pediatric Surgery, Kyushu University School of Medicine, Fukuoka, 812-8582, Japan

    Kouji Masumoto

  13. Department of Neonatology, Kagoshima City Hospital, Kagoshima, 892-8580, Japan

    Takeshi Utsunomiya

  14. Department of Pediatrics, Takamatsu Red Cross Hospital, Takamatsu, 760-0017, Japan

    Hiroko Kouzan

  15. Department of Pediatrics, Numazu City Hospital, Numazu, 410-0302, Japan

    Yumiko Komatsu

  16. Division of Medical Genetics, Saitama Children's Medical Center, Saitama, 339-8551, Japan

    Hirofumi Ohashi

  17. Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, 232-8555, Japan

    Kenji Kurosawa

  18. Department of Pediatrics, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Kenjirou Kosaki

  19. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK

    Anne C Ferguson-Smith

Authors
  1. Masayo Kagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoichi Sekita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gen Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masahito Irie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fumiko Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michiyo Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shunji Yamamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroshi Kishimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masahiro Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yukichi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kentarou Matsuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tsutomu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mika Noguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yoko Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kouji Masumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Takeshi Utsunomiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hiroko Kouzan
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yumiko Komatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Hirofumi Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Kenji Kurosawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kenjirou Kosaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Anne C Ferguson-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Fumitoshi Ishino
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Tsutomu Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Molecular analysis was performed by M.K., Y.S., M.I., F.K., M.O. and S.Y., placental sample collection and preparation by H.K., M.N., Y.T., K.M. and K. Ko., placental pathological examination by K.M., and blood sampling and phenotype assessment by G.N., T.T., M.N., Y.T., K.M., T.U., H.K., Y.K., H.O., K. Ku. and T.O. The study was designed and coordinated by F.I. and T.O. with later input from A.C.F.-S., and the results were interpreted and discussed by A.C.F.-S., F.I. and T.O. The paper was written by T.O.

Corresponding authors

Correspondence to Fumitoshi Ishino or Tsutomu Ogata.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–5, Supplementary Figures 1–3 (PDF 1027 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kagami, M., Sekita, Y., Nishimura, G. et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet 40, 237–242 (2008). https://doi.org/10.1038/ng.2007.56

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2007.56

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing