Aberrant DNA methylation at imprinting control regions in Sotos syndrome

• Project/Area Number: 25461554
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Saga University
• Principal Investigator: Higashimoto Ken 佐賀大学, 医学部, 助教 (30346887)
• Co-Investigator(Renkei-kenkyūsha): MATSUMOTO Naomichi 横浜市立大学, 医学部医学科・遺伝学, 教授 (80325638)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: Sotos症候群 / NSD1 / Beckwith-Wiedemann症候群 / DNAメチル化 / 刷り込み遺伝子 / DMR

Outline of Final Research Achievements

The cause of Sotos syndrome (SoS) and Beckwith-Wiedemann syndrome (BWS) is haploinsufficiency of NSD1 due to intragenic mutations and submicroscopic deletions and aberrant methylation in imprinting regulatory regions at 11p15.5, respectively. These two syndromes belong to overgrowth syndrome and the phenotype is occasionally similar, although the cause is different.
In this study, we showed that aberrant DNA methylation aroused at 11p15.5 in peripheral blood DNA derived from SoS patients. In addition, the HEK293 cells treated by DNA-demethylating agent mimicked the aberrant methylation in SoS patients and the cells increased the expression of growth factor related gene, which is overexpressed in BWS. These suggest that it might be possible to explain the similarity between both syndromes.

Research Products

• [Journal Article] The HUS1B promoter is hypomethylated in the placentas of low-birth-weight infants. (2016)
  • Author(s): Rumbajan JM, Yamaguchi Y, Nakabayashi K, Higashimoto K, Yatsuki H, Nishioka K, Matsuoka K, Aoki S, Toda S, Takeda S, Seki H, Hatada I, Hata K, Soejima H, Joh K.
  • Journal Title: Gene. Volume: 583 Issue: 2 Pages: 141-146
  • DOI: 10.1016/j.gene.2016.02.025
  • Peer Reviewed
• [Journal Article] Novel Nonsense Mutation in the NLRP7 Gene Associated with Recurrent Hydatidiform Mole. (2015)
  • Author(s): Ito Y, Maehara K, Kaneki E, Matsuoka K, Sugahara N, Miyata T, Kamura H, Yamaguchi Y, Kono A, Nakabayashi K, Migita O, Higashimoto K,Soejima H, Okamoto A, Nakamura H, Kimura T, Wake N, Taniguchi T, Hata K
  • Journal Title: Gynecol Obstet Invest. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Beckwith-Wiedemann 症候群（BWS） (2015)
  • Author(s): 東元健、副島英伸
  • Journal Title: 臨床画像 Volume: 31(10増刊号) Pages: 189-191
• [Journal Article] Beckwith-Wiedemann syndrome (2015)
  • Author(s): 東元健、副島英伸
  • Journal Title: 日本臨床 家族性腫瘍学 家族性腫瘍の最新研究動向 Volume: 73(増刊号6) Pages: 59-63
• [Journal Article] Autosomal recessive cystinuria caused by genome-wide paternal uniparental isodisomy in a patient with Beckwith-Wiedemann syndrome. (2015)
  • Author(s): Ohtsuka Y, Higashimoto K, Sasaki K, Jozaki K, Yoshinaga H, Okamoto N, Takama Y, Kubota A, Nakayama M, Yatsuki H, Nishioka K, Joh K, Mukai T, Yoshiura KI, Soejima H.
  • Journal Title: Clinical Genetics Volume: 印刷中
  • Peer Reviewed / 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] Fibroadenoma in a Beckwith-Wiedemann syndrome with paternal uniparental disomy of chromosome 11p15.5. (2014)
  • Author(s): Takama Y, Kubota A, Nakayama M, Higashimoto K, Jozaki K, Soejima H.
  • Journal Title: Pediatrics International Volume: 56 Issue: 6 Pages: 931-934
  • DOI: 10.1111/ped.12406
  • Peer Reviewed
• [Journal Article] Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: Few clinical features suggestive of Beckwith-Wiedemann syndrome. (2013)
  • Author(s): Adachi H, Takahashi I, Higashimoto K, Tsuchida S, Noguchi A, Tamura H, Arai H, Ito T, Masue M, Nishibori H, Takahashi T, Soejima H.
  • Journal Title: Endocr J. Volume: 60 Pages: 403-408
  • NAID: 10031170628
  • Peer Reviewed
• [Journal Article] Novel Mutations of CDKN1C in Japanese Patients with Beckwith-Wiedemann Syndrome. (2013)
  • Author(s): Yatsuki H, Higashimoto K, Jozaki K, Koide K, Okada J, Watanabe Y, Okamoto N, Tsuno Y, Yoshida Y, Ueda K, Shimizu K, Ohashi H, Mukai T, Soejima H.
  • Journal Title: Genes Genom. Volume: 35 Issue: 2 Pages: 141-147
  • DOI: 10.1007/s13258-013-0079-3
  • Peer Reviewed
• [Journal Article] Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-is in a Japanese patient with Perlman syndrome. (2013)
  • Author(s): Higashimoto, K, Maeda, T, Okada, J, Ohtsuka, Y, Sasaki, K, Hirose, A, Nomiyama, M, Takayanagi, T, Fukuzawa, R, Yatsuki, H, Koide, K, Nishioka, K, Joh, K, Watanabe, Y, Yoshiura, ICI, Soejima, H.
  • Journal Title: European Journal of Human Genetics Volume: 21 Issue: 11 Pages: 1316-1319
  • DOI: 10.1038/ejhg.2013.45
  • Peer Reviewed
• [Journal Article] Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing (2013)
  • Author(s): H. Miyazaki, K. Higashimoto, Y. Yada, T. A. Endo, J. Sharif, T. Komori, M. Matsuda, Y. Koseki, M. Nakayama, H. Soejima, H. Handa, H. Koseki, S. Hirose, K. Nishioka
  • Journal Title: PLoS Genet. Volume: 9 Issue: 11 Pages: e1003897-e1003897
  • DOI: 10.1371/journal.pgen.1003897
  • Peer Reviewed
• [Journal Article] Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma (2013)
  • Author(s): Rumbajan JM, Maeda T, Souzaki R, Mitsui K, Higashimoto K, Nakabayashi K, Yatsuki H, Nishioka K, Harada R, Aoki S, Kohashi K, Oda Y, Hata K, Saji T, Taguchi T, Tajiri T, Soejima H, Joh K.
  • Journal Title: BMC Cancer Volume: 13 Issue: 1 Pages: 608-619
  • DOI: 10.1186/1471-2407-13-608
  • Peer Reviewed / Open Access
• [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] Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. (2013)
  • Author(s): Soejima H, Higashimoto K.
  • Journal Title: J Hum Genet Volume: 58 Issue: 7 Pages: 402-409
  • DOI: 10.1038/jhg.2013.51
  • NAID: 10031190033
  • Peer Reviewed
• [Journal Article] Beckwith-Wiedemann症候群とSilver-Russell症候群 (2013)
  • Author(s): 前田寿幸、東元健、副島英伸
  • Journal Title: 小児科臨床 Volume: 66 Pages: 1308-1314
• [Presentation] 間葉性異形成胎盤の分子遺伝学的解析 (2015)
  • Author(s): 青木早織、東元健、樋高秀憲、渡邊英孝、大塚泰史、三嶋博之、吉浦孝一郎、八木ひとみ、西岡憲一、城圭一郎、大場隆、片渕秀隆、副島英伸．
  • Organizer: 第23回日本胎盤学会学術集会
  • Place of Presentation: JA共済ビル カンファレンスホール 東京
  • Year and Date: 2015-11-05
• [Presentation] 間葉性異形成胎盤のゲノム・エピゲノム解析 (2015)
  • Author(s): 青木早織、東元健、樋高秀憲、渡邊英孝、大塚泰史、三嶋博之、吉浦孝一郎、八木ひとみ、西岡憲一、城圭一郎、大場隆、片渕秀隆、副島英伸．
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル 新宿
  • Year and Date: 2015-10-14
• [Presentation] Beckwith-Wiedemann症候群の原因となる片親性父性ダイソミーの切断点領域の解析 (2015)
  • Author(s): 大塚泰史、岡岳彦、川原弘三、八木ひとみ、東元健、副島英伸
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル 新宿
  • Year and Date: 2015-10-14
• [Presentation] 大腸癌におけるインプリントDMRの包括的メチル化解析 (2015)
  • Author(s): 樋高秀憲、東元健、青木早織、渡邊英孝、八木ひとみ、西岡憲一、城圭一郎、前田寿幸、古賀靖大、岩切龍一、能城浩和、藤本一眞、副島英伸
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル 新宿
  • Year and Date: 2015-10-14
• [Presentation] Beckwith-Wiedemann症候群エピ変異症例におけるインプリントDMRの包括的メチル化解析 (2015)
  • Author(s): 前田寿幸、城崎幸介、八木ひとみ、東元 健、松尾宗明、副島英伸
  • Organizer: 第57回日本小児神経学会学術集会
  • Place of Presentation: 帝国ホテル 大阪
  • Year and Date: 2015-05-28
• [Presentation] Clinical and histopathlogical features of placental mesenchymal dysplasia. (2015)
  • Author(s): Aoki S, Ohba T, Okajima M, Higashimoto K, Soejima H, Katabuchi H.
  • Organizer: The 6th Asan-Kumamoto Joint Symposium
  • Place of Presentation: 熊本地域医療ｾﾝﾀｰ新館
  • Year and Date: 2015-05-23
• [Presentation] Beckwith-Wiedemann症候群における新生児期低血糖合併機序の検討 (2015)
  • Author(s): 長嶋一昭、田中大祐、東元 健、八木ひとみ、杉崎 和、田原 裕美子、副島英伸、稲垣暢也
  • Organizer: 第112回日本内科学会総会
  • Place of Presentation: みやこめっせ 京都
  • Year and Date: 2015-04-10
• [Presentation] Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract Polycomb silencing. (2014)
  • Author(s): Kenichi Nishioka、Hitomi Miyazaki, Ken Higashimoto, Yukari Yada, Takaho A. Endo, Jafar Sharif, Manabu Nakayama, Hidenobu Soejima, Haruhiko Koseki, Susumu Hirose．
  • Organizer: 第8回日本エピジェネティクス研究会年会
  • Place of Presentation: 伊藤国際学術研究センター（東京大学構内）
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] Beckwith-Wiedemann症候群と肝芽腫におけるmultiple methylation defectの解析． (2014)
  • Author(s): 前田寿幸、Rumbajan Janette Mareska、東元 健、中林一彦、八木ひとみ、秦健一郎、城圭一郎、副島英伸．
  • Organizer: 第8回日本エピジェネティクス研究会年会
  • Place of Presentation: 伊藤国際学術研究センター（東京大学構内）
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] Practical use of pyrosequencing analysis to detect Moyamoya disease susceptible gene RNF213 variant c.14576G>A. (2013)
  • Author(s): Takamatsu Y, Maeda T, Matsuo M, Higashimoto K, Kawashima M, Matsushima T, Soejima H.
  • Organizer: 3rd International Moyamoya Meeting
  • Place of Presentation: 札幌
• [Presentation] Beckwith-Wiedemann症候群におけるインプリントDMRのマルチローカスメチル化解析 (2013)
  • Author(s): 前田寿幸、東元健、中林一彦、城崎幸介、八木ひとみ、緒方勤、秦健一郎、副島英伸
  • Organizer: 第7回日本エピジェネティクス研究会年会
  • Place of Presentation: 奈良
• [Presentation] H19DMRメチル化異常で発症するインプリント疾患におけるH19DMRの変異解析 (2013)
  • Author(s): 東元 健、城崎幸介、八木ひとみ、古庄知己、松原圭子、山田大輔、前田寿幸、大塚泰史、古関明彦、緒方勤、副島英伸
  • Organizer: 第7回日本エピジェネティクス研究会年会
  • Place of Presentation: 奈良
• [Presentation] シスチン尿症を伴うゲノムワイド父性片親性ダイソミー症例の遺伝子解析 (2013)
  • Author(s): 大塚泰史、佐々木健作、城崎幸介、東元健、岡本信彦、高間勇一、窪田昭男、松本富美、中山雅弘、吉浦孝一郎、副島英伸
  • Organizer: 第48回日本小児腎臓病学会
  • Place of Presentation: 徳島
• [Presentation] 間葉性異形成胎盤における11p15インプリント領域の分子遺伝学的解析 (2013)
  • Author(s): 副島英伸、東元健、城﨑幸介、八木ひとみ、大塚泰史、前田寿幸、青木早織、岡島翠、坂口勲、大場隆、片渕秀隆
  • Organizer: 第21回日本胎盤学会学術集会
  • Place of Presentation: 愛知
• [Presentation] 本邦における間葉性異形成胎盤の臨床像． (2013)
  • Author(s): 青木早織、大場隆、岡島翠、坂口 勲、東元健、副島英伸、福永真治、片渕秀隆．
  • Organizer: 第21回日本胎盤学会学術集会
  • Place of Presentation: 愛知
• [Presentation] シスチン尿症を伴うゲノムワイド父性片親性ダイソミー症例の遺伝子解析 (2013)
  • Author(s): 大塚泰史、佐々木健作、城崎幸介、東元健、岡本信彦、高間勇一、窪田昭男、松本富美、中山雅弘、吉浦孝一郎、副島英伸．
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 宮城
• [Presentation] 間葉性異形成胎盤における11p15刷り込み領域の分子遺伝学的解析． (2013)
  • Author(s): 副島英伸、東元健、城﨑幸介、八木ひとみ、大塚泰史、前田寿幸、青木早織、岡島翠、坂口勲、大場隆、片渕秀隆．
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 宮城
• [Presentation] 胎児発育異常症例の網羅的ゲノム・エピゲノム解析 (2013)
  • Author(s): 佐々木かりん、右田王介、中林一彦、東元健、前田寿幸、橋本和法、松井英雄、副島英伸、高田史男、秦健一郎．
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 宮城
• [Presentation] Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract Polycomb silencing. (2013)
  • Author(s): 宮崎仁美、東元 健、矢田有加里、遠藤高帆、Sharif Jafar、小森敏治, 、松田正史、古関庸子、中山学、副島英伸、半田宏、古関明彦、広瀬進、西岡憲一．
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Book] 別冊日本臨牀 新領域別症候群シリーズNo.29 神経症候群（第２版）Ⅳ–その他の神経疾患を含めて– (2014)
  • Author(s): 東元健、副島英伸
  • Total Pages: 4
  • Publisher: 日本臨牀社
• [Book] 遺伝子医学MOOK25 第2章エピジェネティクスと病気 ４．不妊・先天異常 (2013)
  • Author(s): 東元健、副島英伸
  • Publisher: メディカルドゥ
• [Remarks] 佐賀大学医学部 分子生命科学講座 分子遺伝学 エピジェネティクス分野
  • URL: http://www.biomol.med.saga-u.ac.jp/mbg/index.htm
• [Remarks] 佐賀大学医学部 分子遺伝学 エピジェネティクス分野
  • URL: http://www.biomol.med.saga-u.ac.jp/mbg/index.htm
• [Remarks] 佐賀大学医学部分子生命科学講座 分子遺伝学・エピジェネティクス分野
  • URL: http://www.biomol.med.saga-u.ac.jp/mbg/index.htm