Elucidation of the onset mechanism of human imprinting disorders using the method of methylation analysis with high-density DNA methylation arrays

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K15096
• Research Institution: National Center for Child Health and Development
• Principal Investigator: 鏡 雅代 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 室長 (70399484)
• Co-Investigator(Kenkyū-buntansha): 中林 一彦 国立研究開発法人国立成育医療研究センター, 周産期病態研究部, 室長 (10415557) ; 松原 圭子 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 研究員 (90542952)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: MLID / インプリンティング異常症 / メチル化解析

Outline of Annual Research Achievements

本研究は包括的および網羅的メチル化解析により、8インプリンティング異常症において複数のメチル化異常を示すMultiple Imprintinf Disturbance (MLID)の頻度を明らかとすること、インプリンティング異常症発症機構を明らかにすることを目的とした研究である。我々はこれまでに集積した8インプリンティング異常症約1300名に対し、8インプリンティング異常症責任Differential methylated region (DMR) に対する包括的メチル化解析を行い、38名のMLID症例を同定した。これら、全MLID症例に対し、Infinium Human Methylation 450K BeadChip kit (イルミナ社)を用いた網羅的メチル化解析を施行し、そのうちメチル化可変領域に存在する約750のプローブについてメチル化状態を検討した。14番染色体インプリンティング異常症であるKagami-Ogata症候群 (KOS)とTemple症候群 (TS14) についての網羅的メチル化解析の報告はこれまでになかった。我々はエピ変異で生じたKOS 5症例、TS14 4症例の網羅的メチル化解析を施行し、世界で初めてTS14においてMLIDを同定し、報告した(Kagami et al. Genet Med. 2016)。これらのMLID症例において、既知のMLID責任遺伝子には変異を認めず、epigeneticな原因もしくは未知のgeneticな原因により生じたと予想された。また、同定されたさまざまなMLID症例の中には、構造異常である片親性ダイソミー症例や欠失症例も含まれ、インプリンティング領域間の相互作用の破たんがMLID発症に関連することを示唆した。

Research Products

• [Int'l Joint Research] St Olav's Hospital (Norway)
  • Country Name: Norway
  • Counterpart Institution: St Olav's Hospital
• [Journal Article] Maternal uniparental disomy for chromosome 20: physical and endocrinological characteristics of five patient. (2018)
  • Author(s): Kawasima S, Nakmura A, Inoue T, Matsubara K, Horikawa R, Wakui K, Takano K, Fikushima Y, Tatematsu T, Mizuno S. Tsubaki J, Kure S, Matsubara Y, Ogata T, Fukami M, Kagami M
  • Journal Title: J Clin Endocrinol Metab. Volume: 印刷中 Pages: 印刷中
  • DOI: accepted
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of parent-of-origin methylation using the Illumina Infinium MethylationEPIC array platform. (2018)
  • Author(s): Mora JRH, Tayama C, Sanchez-Delgado M, Monteagudo-Sanchez A, Hata K, Ogata T, Medrano J, Eugenia Poo-Llanill M, Simón C, Moran S, Esteller M, Tenorio J, Lapunzina P, Kagami M, Monk D, Nakabayashi K
  • Journal Title: Epigenomics Volume: 印刷中 Pages: 印刷中
  • DOI: accepted
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case of paternal uniparental isodisomy for chromosome 7 associated with overgrowth. (2018)
  • Author(s): Nakamura A, Muroya K, Ogata-Kawata H, Nakabayashi K, Matsubara K, Ogata T, Kurosawa K, Fukami M, Kagami M.
  • Journal Title: J Med Genet. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1136/jmedgenet-2017-104986.
  • Peer Reviewed
• [Journal Article] Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report. (2018)
  • Author(s): Horikawa Y, Enya M, Komagata M, Hashimotoi KI, Kagami M, Fukami M, Takeda J.
  • Journal Title: Diabetes Ther. Volume: 9 Pages: 421-426
  • DOI: 10.1007/s13300-018-0369-5.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A de novo 50-bp GNAS Intragenic Duplication in a Patient with Pseudohypoparathyroidism Type 1a (2018)
  • Author(s): Suzuki E, Bo R, Sue K, Awano H, Ogata T, Narumi S, Kagami M, Sano S, Fukami M.
  • Journal Title: Cytogenet Genome Res Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1159/000485644.
  • Peer Reviewed
• [Journal Article] A 3-year-old girl with 46,XX,upd(14)mat/47,XX,+14 mosaicism. (2018)
  • Author(s): Ushijima K, Yatsuga S, Nakamura A, Fukami M, Kagami M.
  • Journal Title: J Hum Genet. Volume: 63 Pages: 377-381
  • DOI: 10.1038/s10038-017-0381-z.
  • Peer Reviewed
• [Journal Article] (Epi)genotype-Phenotype Analysis in 69 Japanese Patients With Pseudohypoparathyroidism Type I. (2017)
  • Author(s): Sano S, Nakamura A, Matsubara K, Nagasaki K, Fukami M, Kagami M, Ogata T
  • Journal Title: J Endocr Soc. Volume: 2 Pages: 9-23
  • DOI: 10.1210/js.2017-00293.
  • Peer Reviewed
• [Journal Article] Mosaic upd(14)pat in a patient with mild features of Kagami-Ogata syndrome. (2017)
  • Author(s): Haug MG, Brendehaug A, Houge G, Kagami M, Ogata T
  • Journal Title: Clin Case Rep. Volume: 6 Pages: 91-95
  • DOI: 10.1002/ccr3.1300.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sustained endocrine profiles of a girl with WAGR syndrome. (2017)
  • Author(s): Takada Y, Sakai Y, Matsushita Y, Ohkubo K, Koga Y, Akamine S, Torio M, Ishizaki Y, Sanefuji M, Torisu H, Shaw CA, Kagami M, Hara T, Ohga S.
  • Journal Title: BMC Med Genet. Volume: 18 Pages: 117
  • DOI: 10.1186/s12881-017-0477-5.
  • Peer Reviewed / Open Access
• [Journal Article] Continuous hypomethylation of the KCNQ1OT1:TSS-DMR in monochorionic twins discordant for Beckwith-Wiedemann syndrome. (2017)
  • Author(s): Inoue T, Nakamura A, Matsubara K, Nyuzuki H, Nagasaki K, Oka A, Fukami M, Kagami M.
  • Journal Title: Am J Med Genet A. Volume: 173 Pages: 2847-2850
  • DOI: 10.1002/ajmg.a.38419.
  • Peer Reviewed
• [Journal Article] Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver-Russell syndrome. (2017)
  • Author(s): Dateki S, Kagami M, Matsubara K, Izumi K, Watanabe S, Nakatomi A, Kondoh T, Fukami M, Moriuchi H.
  • Journal Title: J Hum Genet. Volume: 62 Pages: 919-922
  • DOI: 10.1038/jhg.2017.62.
  • Peer Reviewed
• [Journal Article] Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients. (2017)
  • Author(s): Kagami M, Nagasaki K, Kosaki R, Horikawa R, Naiki Y, Saitoh S, Tajima T, Yorifuji T, Numakura C, Mizuno S, Nakamura A, Matsubara K, Fukami M, Ogata T.
  • Journal Title: Genet Med. Volume: 19 Pages: 1356-1366
  • DOI: 10.1038/gim.2017.53.
  • Peer Reviewed / Open Access
• [Journal Article] Genetic heterogeneity of patients with suspected Silver-Russell syndrome: genome-wide copy number analysis in 82 patients without imprinting defects. (2017)
  • Author(s): Inoue T, Nakamura A, Fuke T, Yamazawa K, Sano S, Matsubara K, Mizuno S, Matsukura Y, Harashima C, Hasegawa T, Nakajima H, Tsumura K, Kizaki Z, Oka A, Ogata T, Fukami M, Kagami M.
  • Journal Title: Clin Epigenetics. Volume: 9 Pages: 52
  • DOI: 10.1186/s13148-017-0350-6.
  • Peer Reviewed / Open Access
• [Journal Article] De Novo IGF2 mutation on the paternal allele in a patient with silver-russell syndrome and ectrodactyly. (2017)
  • Author(s): Yamoto K, Saitsu H, Nakagawa N, Nakajima H, Hasegawa T, Fujisawa Y, Kagami M, Fukami M, Ogata T.
  • Journal Title: Hum Mutat. Volume: 38 Pages: 953-958.
  • DOI: 10.1002/humu.23253.
  • Peer Reviewed
• [Journal Article] Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome. (2017)
  • Author(s): Kagami M, Matsubara K, Nakabayashi K, Nakamura A, Sano S, Okamura K, Hata K, Fukami M, Ogata T.
  • Journal Title: Genet Med. Volume: 19 Pages: 476-482.
  • DOI: 10.1038/gim.2016.123.
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis and management of Silver-Russell syndrome: First international consensus statement. (2017)
  • Author(s): Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM et al.
  • Journal Title: Nat Rev Endocrinol. Volume: 13 Pages: 105-124.
  • DOI: 10.1038/nrendo.2016.138.
  • Peer Reviewed / Open Access
• [Presentation] 片親性ダイソミー：両親の年齢と生殖補助医療 (2017)
  • Author(s): 鏡雅代
  • Organizer: 第40回日本分子生物学会
  • Invited
• [Presentation] Kagami-Ogata症候群 (2017)
  • Author(s): 鏡雅代
  • Organizer: 第62回日本人類遺伝学会
  • Invited
• [Presentation] Kagami-Ogata症候群 (2017)
  • Author(s): 鏡雅代
  • Organizer: nordiscience forum 2017
  • Invited
• [Presentation] Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients (2017)
  • Author(s): Masayo Kagami et al.
  • Organizer: ESHG 2017
  • Int'l Joint Research