The role of imprinting control region in regulating imprinting status in 15q11-13 among patients with Prader-Willi syndrome

• Project/Area Number: 25860898
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: MATSUBARA KEIKO 独立行政法人国立成育医療研究センター, その他部局等, 研究員 (90542952)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: Prader-Willi症候群 / インプリンティング異常症 / ＤＮＡメチル化 / エピ変異 / プラダーウィリ症候群 / DNAメチル化 / インプリンティング / Prader Willi症候群 / 遺伝学 / 先天異常

Outline of Final Research Achievements

We performed analysis of endocrinological information and molecular genetic tests on patients with Prader-Willi syndrome (PWS). For molecular analyses, we also utilized samples taken from patients with Angelman syndrome (AS).
First, we performed insulin tolerant test to clarify the feature of hypothalamus, pituitary and adrenal gland axis of PWS patients. Although basal and peak values of ACTH and cortisol were within normal range, cortisol showed prolonged secretion pattern. Secondly, we performed genome wide methylation analysis to reveal DNA methylation pattern among the PWS patients with epimutation or atypical tiny deletion involving PWS-SRO (shortest region of overlapping) and AS-SRO in imprinting control region, and revealed detailed pattern of DNA methylation in 15q11-13 of these patients.Lastly, we detected one patient with Temple syndrome among patients without any of known causes resulting in PWS phenotype.

Research Products

• [Journal Article] Uniparental disomy of chromosome 8 leading to homozygosity of a <i>CYP11B1</i> mutation in a patient with congenital adrenal hyperplasia: Implication for a rare etiology of an autosomal recessive disorder (2014)
  • Author(s): K. Matsubara, N. Kataoka, S. Ogita, S. Sano, T. Ogata, M. Fukami and N. Katsumata
  • Journal Title: Endocrine Journal Volume: 61 Issue: 6 Pages: 629-633
  • DOI: 10.1507/endocrj.EJ13-0509
  • NAID: 130004770452
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions (DMRs) to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations (2014)
  • Author(s): Maeda T, Higashimoto K, Jozaki K, Hitomi H, Nakabayashi K, Makita Y, Tonoki H, Okamoto N, Takada F, Ohashi H, Migita M, Kosaki R, Matsubara K, Ogata T, Matsuo M, Hamasaki Y, Ohtsuka Y, Nishioka K, Joh K, Mukai T, Hata K, Soejima H
  • Journal Title: Genet Med Volume: 16(12) Issue: 12 Pages: 903-912
  • DOI: 10.1038/gim.2014.46
  • Peer Reviewed / Open Access
• [Journal Article] Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell syndrome-compatible phenotype (2014)
  • Author(s): Kagami M, Mizuno S, Matsubars K, Nakabayashi K, Sano S, Fuke T, Fukami M, Ogata T
  • Journal Title: Eur J Hum Genet Volume: 11 Issue: 8 Pages: 1-6
  • DOI: 10.1038/ejhg.2014.234
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Abnormalities in chromosome 6q24 as a cause of early-onset, non-obese, non-autoimmune diabetes mellitus without history of neonatal diabetes. (2014)
  • Author(s): Yorifuji T, Matsubara K, Sakakibara A, Hashimoto Y, Kawakita R, Hosokawa Y, Fujimaru R, Murakami A, Tamagawa N, Hatake K, Nagasaka H, Suzuki J, Urakami T, Izawa M, Kagami M.
  • Journal Title: Diabet Med. Volume: ? Issue: 7 Pages: 963-967
  • DOI: 10.1111/dme.12758
  • Peer Reviewed
• [Journal Article] A novel de novo point mutation of OCT-binding site in the IGF2/H19-imprinting control region in a patient with Beckwith-Wiedemann syndrome. (2013)
  • Author(s): Higashimoto K, Jozaki K, Kosho T, Matsubara K, Sato T, Yamada D, Yatsuki H, Maeda T, Ohtsuka Y, Nishioka K, Joh K, Koseki H, Ogata T, SoejimaH*
  • Journal Title: Clin Genet Volume: in press Issue: 6 Pages: 539-544
  • DOI: 10.1111/cge.12318
  • Peer Reviewed / Open Access
• [Journal Article] Birth seasonality in Prader-Willi syndrome resulting from chromosome 15 microdeletion. (2013)
  • Author(s): Ayabe T, Matsubara K, Ogata T, Ayabe A, Murakami N, Nagai T, Fukami M*
  • Journal Title: Am J Med Genet A Volume: 161 Issue: 6 Pages: 1495-1497
  • DOI: 10.1002/ajmg.a.35893
  • Peer Reviewed
• [Journal Article] Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome (2013)
  • Author(s): T. Fuke, S. Mizuno, T. Nagai, T. Hasegawa, R. Horikawa, Y. Miyoshi, K. Muroya, T. Kondoh, C. Numakura, S. Sato, K. Nakabayashi, C. Tayama, K. Hata, S. Sano, K. Matsubara, M. Kagami, K. Yamazawa, T. Ogata
  • Journal Title: PLoS. One Volume: 8 Issue: 3 Pages: e60105-e60105
  • DOI: 10.1371/journal.pone.0060105
  • Peer Reviewed
• [Journal Article] Advanced maternal age at childbirth and the development of uniparental disomy. A commentary on the proportion of uniparental disomy is increased in Prader-Willi syndrome due to an advanced maternal childbearing age in Korea. (2013)
  • Author(s): Matsubara K, Ogata T*
  • Journal Title: J Hum Genet Volume: 58 Issue: 3 Pages: 118-119
  • DOI: 10.1038/jhg.2013.4
  • NAID: 10031164067
  • Peer Reviewed
• [Presentation] PWS/AS責任領域の非典型的な欠失を有する症例に対する網羅的メチル解析 (2014)
  • Author(s): 松原圭子、伊藤順庸、中林一彦、佐野伸一朗、中村明枝、秦健一郎、緒方勤、深見真紀、斎藤伸治、鏡雅代
  • Organizer: 第59回人類遺伝学会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] 新生児・乳児期に成長障害および筋緊張低下を示すインプリンティング異常症 (2014)
  • Author(s): 松原圭子、水野誠司、鏡雅代
  • Organizer: 第59回 日本未熟児新生児学会
  • Place of Presentation: 愛媛
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Uniparental disomy of chromosome 8 leading to homozygosity of a CYP11B1 mutation in a patient with congenital adrenal hyperplasia (2014)
  • Author(s): Keiko Matsubara, Naoki Kataoka, Satoko Ogita, Shinichiro Sano,Tsutomu Ogata, Maki Fukami, Noriyuki Katsumata
  • Organizer: 第48回小児内分泌学会
  • Place of Presentation: 浜松
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] PWS/AS責任領域の非典型的な欠失を有する症例に対する網羅的メチル解析 (2014)
  • Author(s): 松原圭子、伊藤順庸、中林一彦、佐野伸一朗、中村明枝、秦健一郎、緒方勤、深見真紀、斎藤伸治、鏡雅代
  • Organizer: 第48回小児内分泌学会
  • Place of Presentation: 浜松
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 15番染色体インプリンティング調節領域欠失症例の網羅的メチル化解析 (2014)
  • Author(s): 松原圭子、伊藤順庸、中林一彦、佐野伸一朗、中村明枝、秦健一郎、緒方勤、深見真紀、斎藤伸治、鏡雅代
  • Organizer: 第8回エピジェネティクス研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] Comprehensive analysis for 567 patients with clinical features of human imprinting disorders. (2014)
  • Author(s): Keiko Matsubara, Tomoko Fuke, Shinichiro Sano, Kazuhiko Nakabayashi, Kenichiro Hata, Tsutomu Ogata, Maki Fukami, Masayo Kagami
  • Organizer: 014 PAS annual meeting
  • Place of Presentation: Vancouver
  • Year and Date: 2014-05-03 – 2014-05-06
  • Invited
• [Presentation] 15番染色体インプリンティング調節領域欠失症例の網羅的メチル化解析 (2014)
  • Author(s): 松原圭子、伊藤順庸、中林一彦、佐野伸一朗、中村明枝、秦健一郎、緒方勤、深見真紀、斎藤伸治、鏡雅代
  • Organizer: 第37回日本小児遺伝学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-10
• [Presentation] 生殖補助医療と片親性ダイソミー発症リスク,Risk assessment of ART and its related factors in the development of UPD (2013)
  • Author(s): 松原圭子、福家智子、鏡雅代、深見真紀、永井敏郎、緒方勤
  • Organizer: 第１１６回小児科学会
  • Place of Presentation: 広島
  • Invited
• [Presentation] Prader-Willi症候群患者における副腎機能 (2013)
  • Author(s): 松原圭子、白石昌久、村上信行、土屋貴義、大戸祐二、深見真紀、永井敏郎
  • Organizer: 第１１６回小児科学会
  • Place of Presentation: 広島
• [Presentation] Assessment of adrenal function in patients with Prader-Willi syndrome. (2013)
  • Author(s): Matsubara Keiko, Shiraishi Masahisa, Murakami Nobuyuki, Tsuchiya Takayoshi, Oto Yuji, Kagami Masayo, Fukami Maki, Ogata Tsutomu, Nagai Toshiro
  • Organizer: International Prader-WIlli syndrome organization
  • Place of Presentation: Cambridge
• [Presentation] Assessment of adrenal function in patients with Prader-Willi syndrome. (2013)
  • Author(s): Matsubara Keiko, Shiraishi Masahisa, Murakami Nobuyuki, Tsuchiya Takayoshi, Oto Yuji, Kagami Masayo, Fukami Maki, Ogata Tsutomu, Nagai Toshiro
  • Organizer: European society of pediatric endoclonology
  • Place of Presentation: Milan
• [Presentation] ヒトインプリンティング異常症498症例に対する包括的解析 (2013)
  • Author(s): 松原圭子、福家智子、佐野伸一朗、中林一彦、秦健一郎、緒方勤、深見真紀、鏡雅代
  • Organizer: 第４７回小児内分泌学会
  • Place of Presentation: 東京
• [Presentation] ヒトインプリンティング異常症498症例に対する包括的解析 (2013)
  • Author(s): 松原圭子、福家智子、佐野伸一朗、中林一彦、秦健一郎、緒方勤、深見真紀、鏡雅代
  • Organizer: 第５７回人類遺伝学会
  • Place of Presentation: 仙台