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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.

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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.

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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
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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.

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

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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

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