加齢依存性第1減数分裂不分離と変異型SYCP3

2010 Fiscal Year Annual Research Report

• Project Area: The germline: its developmental cycle and epigenome network
• Project/Area Number: 21028020
• 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: ダウン症候群 / 異数体 / 異数性 / 流産 / 習慣流産 / 不妊症 / 不育症 / SYCP3

Research Abstract

21番染色体のトリソミーは出生児のダウン症候群の原因となるが、他の染色体の数的異常症(異数性)の多くは重篤であり、妊娠早期に流産という転帰をとる。多くの異数性の過剰染色体は、(1)母親由来、(2)第1減数分裂由来、(3)母親の加齢に依存して頻度が増加する、という3つの特徴を有する。卵子形成の第1減数分裂は胎生期から思春期以降の排卵までの間、第1減数分裂前期で長期間停止するため、この期間に染色体の分離になんらかの影響が生じると考えられる。わたしたちは、異数性による流産を繰り返していると思われる習慣流産の患者で、第1減数分裂時の相同染色体の対合に関与するシナプトネマ複合体の蛋白をコードするSYCP3遺伝子の変異を同定した。この変異のひとつはスプライシング部位の変異により第8イントロンの残存をきたし、C末端の変異型SYCP蛋白を産生する。この第8イントロンの残存した転写物は、正常ヒト精巣でもわずかにみられる。健常人でもこのC末端の変異蛋白が産生され、その加齢による蓄積によって、習慣流産患者と同等の病態をきたすという仮説が成り立つ。前年度は、正常マウス性腺でも同じイントロンの残存した転写物が見られることを証明したが、蛋白レベルでは変異蛋白は検出できなかった。本年度は、国外の業者から購入したヒト卵巣サンプルでも同じく第8イントロンの残存した転写物が見られることをRT-PCRにて示した。そこで、ヒトのイントロン残存型蛋白に対するC末端のペプチド抗体を作成し、蛋白レベルでの検出を試みたが、検出できなかった。

Research Products

• [Journal Article] Polymorphism in annexin A5 gene promoter in Japanese women with recurrent pregnancy loss. (2011)
  • Author(s): Miyamura H, Nishizawa H, Ota S, Suzuki M, Inagaki A, Egusa H, Nishiyama S, Kato T, Pryor-Koishi K, Nakanishi I, Fujita T, Imayoshi Y, Markoff A, Yanagihara I, Udagawa Y, Kurahashi H.
  • Journal Title: Mol Hum Reprod Volume: (In press)
  • Peer Reviewed
• [Journal Article] A rare synaptonemal complex protein 3 gene variant is associated with unexplained female infertility. (2011)
  • Author(s): Nishiyama S, Kishi T, Kato T, Suzuki M, Bolor H, Udagawa Y, Kurahashi H.
  • Journal Title: Mol Hum Reprod Volume: (In press)
  • Peer Reviewed
• [Journal Article] Global gene expression profiling in early-stage polycystic kidney disease in the Han : SPRD Cy rat identifies a role for RXR signaling. (2011)
  • Author(s): Kugita M, Nishii K, Morita M, Yoshihara D, Kowa-Sugiyama H, Yamada K, Yamaguchi T, Wallace DP, Calvet JP, Kurahashi H, Nagao S.
  • Journal Title: Am J Physiol Renal Physiol Volume: (In press)
  • Peer Reviewed
• [Journal Article] PPAR-{gamma} agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. (2011)
  • Author(s): Yoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, Yamaguchi T, Calvet JP, Wallace DP, Nagao S.
  • Journal Title: Am J Physiol Renal Physiol Volume: (In press)
  • Peer Reviewed
• [Journal Article] Paternal origin of the de novo constitutional t(11;22)(q23;q11). (2010)
  • Author(s): Ohye T, Inagaki H, Kogo H, Tsutsumi M, Kato T, Tong M, Macville M, Medne L, Zackai EH, Emanuel BS, Kurahashi H.
  • Journal Title: Eur J Hum Genet Volume: 18 Pages: 783-7
  • Peer Reviewed
• [Journal Article] Polymorphisms of the 22q11.2 breakpoint region influence the frequency of de novo constitutional t(11;22)s in sperm. (2010)
  • Author(s): Tong M, Kato T, Yamada K, Inagaki H, Kogo H, Ohye T, Tsutsumi M, Wang J, Emanuel BS, Kurahashi H.
  • Journal Title: Hum Mol Genet Volume: 19 Pages: 2630-7
  • Peer Reviewed
• [Journal Article] A new palindrome-mediated recurrent translocation with 3:1 meiotic non-disjunction : the t(8;22)(q24.13;q11.21). (2010)
  • Author(s): Sheridan MB, Kato T, Haldeman-Englert C, Jalali GR, Milunsky JM, Zou Y, Klaes R, Gimelli S, Gemmill RM, Drabkin HA, Hacker AM, Brown J, Tomkins D, Shaikh TH, Kurahashi H, Zackai EH, Emanuel BS.
  • Journal Title: Am J Hum Genet Volume: 87 Pages: 209-18
  • Peer Reviewed
• [Journal Article] The constitutional t(11;22) : implications for a novel mechanism responsible for gross chromosomal rearrangement. (2010)
  • Author(s): Kurahashi H, Inagaki H, Kogo H, Ohye T, Tsutsumi M, Kato T, Tong M, Emanuel BS.
  • Journal Title: Clin Genet Volume: 78 Pages: 299-309
  • Peer Reviewed
• [Journal Article] Screening of genes involved in chromosome segregation during meiosis I : towards the identification of genes responsible for infertility in humans. (2010)
  • Author(s): Kogo H, Kowa-Sugiyama H, Yamada K, Bolor H, Tsutsumi M, Ohye T, Inagaki H, Taniguchi M, Toda T, Kurahashi H.
  • Journal Title: J Hum Genet Volume: 55 Pages: 293-9
  • Peer Reviewed
• [Journal Article] CD9 gene variations are not associated with female infertility in humans. (2010)
  • Author(s): Nishiyama S, Kishi T, Kato T, Suzuki M, Nishizawa H, Pryor-Koishi K, Sawada T, Nishiyama Y, Iwata N, Udagawa Y, Kurahashi H.
  • Journal Title: Gynecol Obstet Invest Volume: 69 Pages: 116-21
  • Peer Reviewed
• [Journal Article] Genetic variation in the indoleamine 2,3-dioxygenase gene in pre-eclampsia. (2010)
  • Author(s): Nishizawa H, Kato T, Ohta S, Nishiyama S, Pryor-Koishi K, Suzuki M, Tsutsumi M, Inagaki H, Kurahashi H, Udagawa Y.
  • Journal Title: Am J Reprod Immunol Volume: 64 Pages: 68-76
  • Peer Reviewed
• [Journal Article] Genetic variation in the indoleamine 2,3-dioxygenase gene in pre-eclampsia (Reply). (2010)
  • Author(s): Nishizawa H, Kurahashi H.
  • Journal Title: Am J Reprod Immunol Volume: 64 Pages: 317
  • Peer Reviewed
• [Journal Article] Polycystic kidney disease in Han : SPRD Cy rats is associated with elevated expression and mislocalization of SamCystin. (2010)
  • Author(s): Nagao S, Morita M, Kugita M, Yoshihara D, Yamaguchi T, Kurahashi H, Calvet JP, Wallace DP.
  • Journal Title: Am J Physiol Renal Physiol Volume: 299 Pages: F1078-86
  • Peer Reviewed
• [Journal Article] Urinary neutrophil gelatinase-associated lipocalin is a potential non-invasive marker for renal scarring in patients with vesicoureteral reflux. (2010)
  • Author(s): Ichino M, Kusaka M, Kuroyanagi Y, Mori T, Morooka M, Sasaki H, Shiroki R, Shishido S, Kurahashi H, Hoshinaga K.
  • Journal Title: J Urol Volume: 183 Pages: 2001-7
  • Peer Reviewed
• [Journal Article] Serum tissue inhibitor of metalloproteinases 1 (TIMP-1) predicts organ recovery from delayed graft function after kidney transplantation from donors after cardiac death. (2010)
  • Author(s): Kusaka M, Kuroyanagi Y, Ichino M, Sasaki H, Maruyama T, Hayakawa K, Shiroki R, Sugitani A, Kurahashi H, Hoshinaga K.
  • Journal Title: Cell Transplant Volume: 19 Pages: 723-9
  • Peer Reviewed
• [Journal Article] Correlation of axillary osmidrosis to a SNP in the ABCC11 gene determined by the smart-amplification process (SMAP). (2010)
  • Author(s): Inoue Y, Mori T, Sakurai A, Mitani Y, Toyoda Y, Ishikawa T, Hayashizaki Y, Yoshimura Y, Kurahashi H, Sakai Y.
  • Journal Title: J Plast Reconstr Aesthet Surg Volume: 63 Pages: 1369-74
  • Peer Reviewed
• [Journal Article] Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure. (2010)
  • Author(s): Ohtsuki M, Morimoto S, Izawa H, Ismail TF, Ishibashi-Ueda H, Kato Y, Horii T, Isomura T, Suma H, Nomura M, Hishida H, Kurahashi H, Ozaki Y.
  • Journal Title: Int J Cardiol Volume: 145 Pages: 333-4
  • Peer Reviewed
• [Presentation] Mutation of the SYCP3 gene in women with recurrent pregnancy loss (2010)
  • Author(s): Kurahashi H, Tsutsumi M, Egusa H, Nishiyama S, Suzuki M, Kogo H, Inagaki H, Ohye T.
  • Organizer: International Symposium on Epigenome Network, Development and Reprogramming of Germ Cells.
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 20101122-20101124
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans. (2010)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H.
  • Organizer: The American Society of Human Genetics 60th Annual Meeting
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20101102-20101106
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans. (2010)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H.
  • Organizer: The 7th 3R Symposium
  • Place of Presentation: Toyama, Japan
  • Year and Date: 20101026-20101030
• [Presentation] Palindrome-mediated chromosomal translocation in humans. (2010)
  • Author(s): Kurahashi H.
  • Organizer: FASEB Summer Research Conferences. Biological Impact of Alternatively Structured DNA.
  • Place of Presentation: Steamboat Springs, Colorado, USA(招待講演)
  • Year and Date: 20100705-20100710
• [Presentation] Paternal origin of the de novo constitutional t(11;22)(q23;q11). (2010)
  • Author(s): Ohye T, Inagaki H, Kogo H, Tsutsumi M, Kato T, Tong M, Macville MVE, Medne L, Zackai EH, Emanuel BS, Kurahashi H.
  • Organizer: European Society of Human Genetics Conference 2010.
  • Place of Presentation: Gothenburg, Sweden
  • Year and Date: 20100612-20100615
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans. (2010)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H.
  • Organizer: Keystone Symposia : Functional Consequences of Structural Variation in the Crenome
  • Place of Presentation: Steamboat Springs, Colorado, USA
  • Year and Date: 20100108-20100113