習慣流産をおこすＧ４四重鎖ＤＮＡ多型

2012 Fiscal Year Annual Research Report

• Project/Area Number: 23659182
• Research Institution: Fujita Health University
• Principal Investigator: 倉橋 浩樹 藤田保健衛生大学, 総合医科学研究所, 教授 (30243215)
• Keywords: 習慣流産 / アネキシンA5 / グアニン4重鎖 / プロモーター / 多型 / 円旋光二色性

Research Abstract

習慣流産は多因子疾患であるが、胎盤における過凝固も要因のひとつである。私たちは以前の研究で、胎盤性抗凝固因子であるアネキシンA5遺伝子のプロモーター領域にある遺伝子多型が習慣流産と関連し、女性が少数アリルを持つと流産のリスクが増加することを示した。このプロモーター領域の多型の位置にはグアニン4重鎖形成のコンセンサス配列がある。近年、プロモーター領域のグアニン4重鎖構造の転写調節作用が注目されている。本研究では、プロモーター領域の多型がこのコンセンサスを変化させ、グアニン4重鎖の形成しやすさに影響し、その結果、少数アリルからのアネキシンA5の発現量が低下することが胎盤における過凝固をひきおこし、流産のリスクが増加するという仮説を証明する。昨年度は、胎盤でのアネキシンA5の発現量をqRT-PCRにて検討したところ、少数アリルからの発現量がすくないことを、胎盤でのqRT-PCRで示し、ルシフェラーゼシステムを用いて、少数アリルのプロモーター活性が低いことを示した。また、円旋光二色性（CD）によりグアニン4重鎖形成能を検討したところ、多数アリルは生理的条件でグアニン4重鎖を形成し、少数アリルは多数アリルよりもグアニン4重鎖形成能が低下していた。本年度は、ルシフェラーゼシステムで、グアニン4重鎖形成を阻害するような変異を導入すると、少数アリルと同程度にルシフェラーゼ活性が低下した。グアニン4重鎖結合剤TMPyP4を加えるとルシフェラーゼ活性が低下し、絨毛細胞株でアネキシンA5の発現量が低下した。以上より、少数アリルはグアニン4重鎖形成能が低下することでプロモーター活性が低下し、アネキシンA5の発現量が低下し、胎盤内で過凝固になり、その結果、流産を起こしやすい状態になっていることが示唆された。

Research Products

• [Journal Article] Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations (2013)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H
  • Journal Title: Nat Commun Volume: 4 Pages: 1592
  • DOI: 10.1038/ncomms2595
  • Peer Reviewed
• [Journal Article] MTA3 regulates CGB5 and Snail genes in trophoblast (2013)
  • Author(s): Chen Y, Miyazaki J, Nishizawa H, Kurahashi H, Leach R, Wang K
  • Journal Title: Biochem Biophys Res Commun Volume: In press Pages: In press
  • DOI: pii: S0006-291X(13)00412-9. 10.1016/j.bbrc.2013.02.102.
  • Peer Reviewed
• [Journal Article] Acute eosinophilic pneumonia occurring in a dedicator of cytokinesis 8 (DOCK8) deficient patient (2013)
  • Author(s): Tsuge I, Ito K, Ohye T, Kando N, Kondo Y, Nakajima Y, Inuo C, Kurahashi H, Urisu A
  • Journal Title: Pediatric Pulmonology Volume: In press Pages: In press
  • Peer Reviewed
• [Journal Article] Chromosomal translocations and palindromic AT-rich repeats (2012)
  • Author(s): Kato T, Kurahashi H, Emanuel BS
  • Journal Title: Curr Opin Genet Dev Volume: 22 Pages: 221-228
  • DOI: doi:10.1016/j.gde2012.02.004.
  • Peer Reviewed
• [Journal Article] HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes (2012)
  • Author(s): Kogo H, Tsutsumi M, Ohye T, Inagaki H, Abe T, Kurahashi H
  • Journal Title: Genes Cells Volume: 17 Pages: 439-454
  • DOI: doi:10.1111/j.1365-2443.2012.01600.x
  • Peer Reviewed
• [Journal Article] HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity (2012)
  • Author(s): Kogo H, Tsutsumi M, Ohye T, Inagaki H, Kiyonari H, Kurahashi H
  • Journal Title: Genes Cells Volume: 17 Pages: 897-912
  • DOI: doi:10.1111/gtc.12005.
  • Peer Reviewed
• [Journal Article] Failure of homologous synapsis and sex-specific reproduction problems (2012)
  • Author(s): Kurahashi H, Kogo H, Tsutsumi M, Inagaki H, Ohye T
  • Journal Title: Front Genet Volume: 3 Pages: 112
  • DOI: doi:10.3389/ fgene.2012.00112
  • Peer Reviewed
• [Journal Article] Molecular basis of maternal age-related increase in oocyte aneuploidy (2012)
  • Author(s): Kurahashi H, Tsutsumi M, Nishiyama S, Kogo H, Inagaki H, Ohye T
  • Journal Title: Congenit Anom (Kyoto) Volume: 52 Pages: 8-15
  • DOI: doi:10.1111/j.1741-4520.2011.00350.x
  • Peer Reviewed
• [Journal Article] Serum neutrophil gelatinase-associated lipocalin during the early postoperative period predicts the recovery of graft function after kidney transplantation from donors after cardiac death (2012)
  • Author(s): Kusaka M, Iwamatsu F, Kuroyanagi Y, Nakaya M, Ichino M, Marubashi S, Nagano H, Shiroki R, Kurahashi H, Hoshinaga K
  • Journal Title: J Urol Volume: 187 Pages: 2261-2267
  • DOI: doi:10.1016/j.juro.2012.01.033.
  • Peer Reviewed
• [Journal Article] Global gene expression profiling in PPAR-γ agonist-treated kidneys in an orthologous rat model of human autosomal recessive polycystic kidney disease (2012)
  • Author(s): Yoshihara D, Kugita M, Yamaguchi T, Aukema HM, Kurahashi H, Morita M, Hiki Y,Calvet JP, Wallace DP, Toyohara T, Abe T,Nagao S.
  • Journal Title: PPAR Research Pages: 695898
  • DOI: doi:10.1155/2012/695898
  • Peer Reviewed
• [Journal Article] Screening of genes involved in chromosome segregation during meiosis I: in vitro gene transfer to mouse fetal oocytes (2012)
  • Author(s): Tsutsumi M, Kowa-Sugiyama H, Bolor H, Kogo H, Inagaki H, Ohye T, Yamada K, Taniguchi-Ikeda M, Toda T, Kurahashi H
  • Journal Title: J Hum Genet Volume: 57 Pages: 515-22
  • DOI: 10.1038/jhg.2012.61
  • Peer Reviewed
• [Journal Article] Mechanism of complex gross chromosomal rearrangements: A commentary on Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation (2012)
  • Author(s): Kurahashi H, Ohye T, Inagaki H, Kogo H, Tsutsumi M
  • Journal Title: J Hum Genet Volume: 57 Pages: 81-3
  • DOI: 10.1038/jhg.2011.143
• [Journal Article] Upregulation of HtrA4 in the placentas of patients with severe pre-eclampsia (2012)
  • Author(s): Inagaki A, Nishizawa H,Ota S,SuzukiM,Inuzuka H, Miyamura H, Sekiya T, Kurahashi H, Udagawa Y
  • Journal Title: Placenta Volume: 33 Pages: 919-26
  • DOI: 10.1016/j.placenta.2012.08.003
  • Peer Reviewed
• [Journal Article] A Functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan (2012)
  • Author(s): Ahmed WA, Tsutsumi M, Nakata S, Mori T, Nishimura Y, Fujisawa T, Kato I, Nakashima M, Kurahashi H, Suzuki K
  • Journal Title: Laryngoscope Volume: 122 Pages: 925-9
  • DOI: 10.1002/lary.23179
  • Peer Reviewed
• [Presentation] Pathogenic exon-trapping by SVA retrotransposon and rescue in Faukuyama muscular dystrophy (2012)
  • Author(s): Taniguchi M, Kobayashi K, Kanagawa M, Yu CC, Oda T, Kuga A, Kurahashi H, Akmen HO, DiMauro S, Yokota T, Takeda S, Toda T
  • Organizer: ASHG 2012, annual meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20121106-20121110
• [Presentation] Polymorphisms in the ANXA5gene promoter in Japanese women with preeclampsia (2012)
  • Author(s): Miyamura H, Nishizawa H, Ota S,Suzuki M, Inagaki A, Egusa H, Nishiyama S, Kurahashi H, Udagawa Y.
  • Organizer: The XX FIGO World Congress
  • Place of Presentation: Rome, Italy
  • Year and Date: 20121007-12
• [Presentation] Mechanism of recurrent translocation t(11;22) initiated by cruciform conformation of palindromes (2012)
  • Author(s): Inagaki, H., Ohye, T., Kogo, H., Tsutsum,i Kurahashi H
  • Organizer: FASEB SRC:“Dynamic DNA structures in biology”
  • Place of Presentation: Saxtons River, USA
  • Year and Date: 20120717-20120722
• [Presentation] Polymorphisms in the ANXA5gene promoter in Japanese women with pre-eclampsia (2012)
  • Author(s): Kurahashi H, Miyamura H, Nishizawa H, Ota S,Suzuki M, Inagaki A, Egusa H, Nishiyama S, Udagawa Y
  • Organizer: European Society of Human Genetics Conference 2012
  • Place of Presentation: Nurnberg, Germany
  • Year and Date: 20120623-20120626
• [Remarks] 藤田保健衛生大学・総合医科学研究所
  • URL: http://www.fujita-hu.ac.jp/ICMS/
• [Remarks] 藤田保健衛生大学・総合医科学研究所・分子遺伝学研究部門
  • URL: http://www.fujita-hu.ac.jp/~genome/mg/