変異型SYCP3が相同染色体分配に与えるインパクトと習慣流産

• Project Area: The germline: its developmental cycle and epigenome network
• Project/Area Number: 23013019
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥6,400,000 (Direct Cost: ¥6,400,000); Fiscal Year 2012: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2011: ¥3,200,000 (Direct Cost: ¥3,200,000)
• Keywords: 異数体 / 習慣流産 / SYCP3 / 対合 / 卵巣 / 器官培養 / 減数分裂 / 遺伝子導入

Research Abstract

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3名の患者で、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。これらの変異はすべてスプライシング部位の変異で、第8イントロンの残存、もしくは、第8エクソンのスキップをきたし、C末端の変異型SYCP蛋白を産生する。これまでの研究で、これらのC末端の変異蛋白が優性阻害効果によって、正常のSYCP3蛋白のファイバー形成を阻害することを、細胞株を用いた実験で証明している。しかし、実際の減数分裂時の卵細胞における変異型SYCP3蛋白の挙動、染色体分配に対する影響に関しては未解明である。そこで、本研究では、これら変異型SYCP3蛋白をマウスの卵細胞に強制発現させ、減数分裂細胞レベルでの異常の検出を試み、習慣流産の発症メカニズムに迫ることを目的としている。昨年度に確立した、マウス卵巣の器官培養の実験系を用いて、習慣流産の患者でみられた変異遺伝子を強制発現させ、変異型SYCP3蛋白の作用を解析した。正常SYCP3蛋白は染色体の軸上に同定され、内因性のSYCP3蛋白とともにシナプトネマ複合体を形成したが、変異型SYCP3蛋白を発現した卵細胞はシナプトネマ複合体が太く、形態異常を呈したが対合した。
ただ、同じ時期の卵細胞で対合染色体を数えると正常よりやや少なかった。対合した染色体ではMLH1 fociは正常であった。以上より、変異があると変異型蛋白の優性阻害効果により対合が遅れることがその後のキアズマ形成に影響し不分離を起こす染色体の頻度が増加すると推測された。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

1年目は実験系の確立に、2年目は実際の変異蛋白の挙動の観察にあてる計画を立てていたが、予定通り、2年間で卵巣の器官培養による実験系の確立、患者の遺伝子変異による変異型蛋白の作用が観察できた。

Strategy for Future Research Activity

異数性を繰り返す習慣流産患者での本遺伝子の変異は頻度が高くないことがわかった。順次、他の減数分裂特異的遺伝子の変異スクリーニングや、エクソーム解析をおこない、新たな習慣流産の原因遺伝子を同定し、習慣流産の発生メカニズムに迫る予定である。

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 Issue: 1 Pages: 1592-1592
  • 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) Issue: 4 Pages: 379-384
  • DOI: 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)
  • 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 Issue: 6 Pages: 439-454
  • 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 Issue: 11 Pages: 897-912
  • DOI: 10.1111/gtc.12005
  • 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 Issue: 8 Pages: 515-522
  • DOI: 10.1038/jhg.2012.61
  • NAID: 10031056588
  • 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 Issue: 2 Pages: 81-83
  • DOI: 10.1038/jhg.2011.143
  • NAID: 10030711395
  • 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 Issue: 1 Pages: 8-15
  • DOI: 10.1111/j.1741-4520.2011.00350.x
  • 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: 112-112
  • 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 Issue: 3 Pages: 221-228
  • DOI: 10.1016/j.gde.2012.02.004
  • Peer Reviewed
• [Journal Article] Upregulation of HtrA4 in the placentas of patients with severe pre-eclampsia (2012)
  • Author(s): Inagaki A, Nishizawa H, Ota S, Suzuki M, Inuzuka H, Miyamura H, Sekiya T, Kurahashi H, Udagawa Y
  • Journal Title: Placenta Volume: 33 Issue: 11 Pages: 919-926
  • DOI: 10.1016/j.placenta.2012.08.003
  • 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 Issue: 6 Pages: 2261-2267
  • DOI: 10.1016/j.juro.2012.01.033
  • 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 Issue: 4 Pages: 925-929
  • DOI: 10.1002/lary.23179
  • Peer Reviewed
• [Journal Article] Global Gene ExpressionProfiling in PPAR-γ Agonist-TreatedKidneys 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 Res Volume: 2012 Pages: 695898-695898
  • DOI: 10.1155/2012/695898
  • Peer Reviewed
• [Journal Article] Characterization of a novel mouse gene encoding an SYCP3-like protein that re-localizes from the XY body to the nucleolus during prophase of male meiosis I (2011)
  • Author(s): Tsutsumi M, Kogo H, Kowa-Sugiyama H, Inagaki H, Ohye T, Kurahashi H
  • Journal Title: Biol Reprod Volume: 85 Issue: 1 Pages: 165-171
  • DOI: 10.1095/biolreprod.110.087270
  • Peer Reviewed
• [Journal Article] Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy (2011)
  • Author(s): Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S, Kaji R, Yokota T, Takeda S, Toda T
  • Journal Title: Nature Volume: 478 Issue: 7367 Pages: 127-131
  • DOI: 10.1038/nature10456
  • Peer Reviewed
• [Journal Article] A rare synaptonemal complex protein 3 gene variant in 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: 17 Issue: 4 Pages: 266-271
  • DOI: 10.1093/molehr/gaq098
  • Peer Reviewed
• [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: 17 Issue: 7 Pages: 447-452
  • DOI: 10.1093/molehr/gar008
  • Peer Reviewed
• [Journal Article] DNA secondary structure is influenced by genetic variation and alters susceptibility to de novo translocation (2011)
  • Author(s): Kato T, Inagaki H, Tong M, Kogo H, Ohye T, Yamada K, Tsutsumi M, Emanuel BS, Kurahashi H
  • Journal Title: Mol Cytogenet Volume: 4 Issue: 1 Pages: 18-18
  • DOI: 10.1186/1755-8166-4-18
  • Peer Reviewed
• [Journal Article] Comparative gene expression profiling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction (2011)
  • Author(s): Nishizawa H, Ota S, Suzuki M, Kato T, Sekiya T, Kurahashi H, Udagawa Y
  • Journal Title: Reprod Biol Endocrinol Volume: 9 Issue: 1 Pages: 107-107
  • DOI: 10.1186/1477-7827-9-107
  • Peer Reviewed
• [Journal Article] Impact of indoleamine 2,3-dioxygenase on the antioxidant system in the placentas of severely pre-eclamptic patients (2011)
  • Author(s): Nishizawa H, Suzuki M, Pryor-Koishi K, Sekiya T, Tada S, Kurahashi H, Udagawa Y
  • Journal Title: Syst Biol Reprod Med Volume: 57 Issue: 4 Pages: 174-178
  • DOI: 10.3109/19396368.2011.587590
  • 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: 300 Issue: 1 Pages: F177-F188
  • DOI: 10.1152/ajprenal.00470.2010
  • 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: 300 Issue: 2 Pages: F465-F474
  • DOI: 10.1152/ajprenal.00460.2010
  • Peer Reviewed
• [Journal Article] Lack of Association between Orexin Receptor Genes Polymorphisms and Obstructive Sleep Apnea Syndrome in Japanese (2011)
  • Author(s): Ahmed WA, Mori T, Nishimura Y, Kitanaka T, Kato T, Bhardwaj KA, Kurahashi H, Suzuki K
  • Journal Title: Sleep Biol Rhythms Volume: 9 Pages: 73-77
  • Peer Reviewed
• [Journal Article] Chromosomal translocations and palindromic AT-rich repeats
  • Author(s): Kato T, Kurahashi H, Emanuel BS
  • Journal Title: Curr Opin Genet Dev Volume: (In press)
  • Peer Reviewed
• [Journal Article] HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes
  • Author(s): Kogo H, Tsutsumi M, Ohye T, Inagaki H, Abe T, Kurahashi H
  • Journal Title: Genes Cells Volume: (In press)
  • Peer Reviewed
• [Journal Article] A Functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan
  • 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: (In press)
  • 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
  • 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: (In press)
  • Peer Reviewed
• [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
• [Presentation] Mechanism of recurrent translocation t(11; 22) initiated by cruciform conformation of palindromes (2012)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kurahashi H
  • Organizer: FASEB SRC : "Dynamic DNA structures in biology"
  • Place of Presentation: Saxtons River, USA
• [Presentation] Polymorphisms in the ANXA5gene promoter in Japanese women with preeclampsia (2012)
  • Author(s): Miyamura H, Nishizavva 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
• [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
• [Presentation] Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss (2011)
  • Author(s): Kurahashi H, 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, Negi R, Markoff A, Yanagihara I, Udagawa, Y
  • Organizer: European Society of Human Genetics Conference 2011.
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] Polymorphisms in the 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
  • Organizer: 59th Annual Clinical Meeting, ACOG
  • Place of Presentation: Washington DC, USA
• [Presentation] Polymorphisms in the 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
  • Organizer: 27th Annual Meeting of ESHRE-Stockholm 2011
  • Place of Presentation: Stockholm, Sweden
• [Presentation] Mechanism of recurrent translocation t(11;22) initiated by cruciform conformation of palindromic sequences (2011)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
• [Presentation] Identification of a recombination hotspot sequence at the breakpoint region of the 22q11 deletion using a yeast model (2011)
  • Author(s): Ohye T, Inagaki H, Kogo H, Tsutsumi M, Emanuel BS, Kurahashi H
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
• [Presentation] HORMAD1-deficiency causes azoospermia in males and pregnancy loss in females (2011)
  • Author(s): Kogo H, Tsutsumi M, Ohye T, Inagaki H, Kurahashi H
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
• [Presentation] Identification of a novel palindrome mediated translocation associated with the t(3;8) of hereditary renal cancer (2011)
  • Author(s): Kato T, Sheridan MB, Hacker AM, Inagaki H, Glover TW, Plon SE, Drabkin HA, Gemmill RM, Kurahashi H, Emanuel BS
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
• [Presentation] Mutation in the SYCP3 gene identified in a woman with recurrent pregnancy loss affect the synaptonemal complex conformation at meiotic prophase I (2011)
  • Author(s): Tsutsumi M, Kogo H, Inagaki H, Ohye T, Kurahashi H
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
• [Presentation] HORMAD1-dependent synapsis checkpoint in mammalian meiosis (2011)
  • Author(s): Kogo H, Tsutsumi M, Ohye T, Inagaki H, Kurahashi H
  • Organizer: 2011 FASEB Summer Research Conferences, Genetic Recombination & Genome Rearrangements
  • Place of Presentation: Steamboat Springs, USA
• [Presentation] 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
  • Organizer: World Congress of Nephrology 2011
  • Place of Presentation: Vancouver, Canada
• [Presentation] Global gene expression profiling in kidneys of PPAR-gamma agonist-treated PCK rats, an orthologous model of human ARPKD (2011)
  • Author(s): Yoshihara D, Kugita M, Kurahashi H, Morita M, Hiki Y, Yamaguchi T, Aukema HM, Wallace DP, Calvet JP, Toyohara T, Abe T, Nagao S
  • Organizer: American Society of Nephrology 44th Annual Meeting & Scientific Exposition
  • Place of Presentation: Philadelphia, PA USA
• [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] 分子遺伝学研究部門
  • URL: http://www.fujita-hu.ac.jp/~genome/mg/
• [Remarks]
  • URL: http://www.fujita-hu.ac.jp/ICMS/
• [Remarks] 分子遺伝学研究部門
  • URL: http://www.fujita-hu.ac.jp/~genome/mg/