コピー数多型は相同染色体対合・組換え不全によるヒト不妊・不育症をおこすか?

• Project/Area Number: 21659085
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Human genetics
• 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): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 2010: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2009: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: コピー数多型 / 不妊症 / 不育症 / 習慣流産 / 無精子症 / 対合 / アレイCGH / 減数分裂

Research Abstract

ヒト不妊症や習慣流産は多因子疾患であり、種々の生活習慣病と同様に後天性の環境因子とともに、先天性の遺伝因子の影響があると考えられている。第1減数分裂前期のイベント(姉妹染色体間の合着、相同染色体間の対合、組換え)は減数分裂における染色体の正しい分配に重要であることが知られている。これらの現象に関わる遺伝子のノックアウトマウスでは雄は無精子症、メスは卵の染色体異数性をきたし、ヒトの習慣流産に類似の表現型を呈する。本研究で解析した症例は近親婚(いとこ婚)の兄妹例で、男性は無精子症による不妊症、女性は習慣流産の表現型を呈した。この習慣流産の女性はパートナーとともに染色体所見は正常であるが、その流産胎児の染色体所見は毎回異なる染色体のトリソミーを繰り返しており、第1減数分裂前期に機能する遺伝子異常の劣性変異の存在が示唆された。本症例の不妊症・習慣流産の原因遺伝子を同定すべく、マイクロアレイを用いたゲノムワイドのSNP解析を行い、原因遺伝子座位のホモ接合性マッピングをおこなった。その結果、予想通り、全ゲノムの約1/16の領域でSNPは連続してホモを呈していた。このホモ領域に位置する、既知の第1減数分裂前期に特異的に発現する遺伝子3つ(HORMAD1, STAG3, MSH5)に関してサンガー・シークエンス法にて変異のスクリーニングを行ったが、遺伝子変異は同定できなかった。今後は、エクソーム解析をおこなう必要があると考えられた。

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, Nshii 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, Tada T, Kurahashi H.
  • Journal Title: J Hum Genet Volume: 55 Pages: 293-9
  • NAID: 10030734983
  • 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: 317-317
  • 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
  • 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
• [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: Gynecologic and Obstetric Investigation 69 Pages: 116-121
  • Peer Reviewed
• [Journal Article] Mutations of the SYCP3 gene in women with recurrent pregnancy loss (2009)
  • Author(s): Bolor H, Mori T, Nishiyama S, Ito Y, Hosoba E, Inagaki H, Kogo H, Ohye T, Makiko T, Kato T, Tong M, Nishizawa H, Pryor-Koishi K, Kitaoka E, Sawada T, Nishiyama Y, Udagawa Y, Kurahashi H
  • Journal Title: American Journal of Human Genetics 84 Pages: 14-20
  • Peer Reviewed
• [Journal Article] Chromosomal instability mediated by non-B DNA : Cruciform conformation and not DNA sequence is responsible for recurrent translocation in humans (2009)
  • Author(s): Inagaki H, Ohye T, Kogo H, Kato T, Bolor H, Taniguchi M, Shaikh TH, Emanuel BS, Kurahashi H
  • Journal Title: Genome Research 19 Pages: 191-198
  • Peer Reviewed
• [Journal Article] Impaired DNA replication prompts deletions within palindrom is sequences, but does not induce translocations in human cells (2009)
  • Author(s): Kurahashi H, Inagaki H, Kato T, Hosoba E, Kogo H, Ohye T, Tsutsumi M, Bolor H, Tong M, Emanuel BS
  • Journal Title: Human Molecular Genetics 18 Pages: 3397-3406
  • Peer Reviewed
• [Journal Article] Recent advance in our understanding of the molecular nature of chromosomal abnormalities (2009)
  • Author(s): Kurahashi H, Bolor H, Kato T, Kogo H, Tsutsumi M, Inagaki H, Ohye T
  • Journal Title: Journal of Human Genetics 54 Pages: 253-260
  • NAID: 10030730167
  • Peer Reviewed
• [Journal Article] Analysis of nitric oxide metabolism as a placental or maternal factor underlying the etiology of pre-eclampsia (2009)
  • Author(s): Nishizawa H, Pryor-Koishi K, Suzuki M, Kato T, Sekiya T, Tada S, Kurahashi H, Udagawa Y
  • Journal Title: Gynecologic and Obstetric Investigation 68 Pages: 239-247
  • Peer Reviewed
• [Journal Article] Increased urinary neutrophil gelatinase-associated lipocalin levels in a rat model of upper urinary tract infection (2009)
  • Author(s): Ichino M, Kuroyanagi Y, Kusaka M, Mori T, Ishikawa K, Shiroki R, Kurahashi H, Hoshinaga K
  • Journal Title: Journal of Urology 181 Pages: 2326-2331
  • Peer Reviewed
• [Journal Article] Global expression profiles in 1-hour biopsy specimens of human kidney transplantation from donors after cardiac death (2009)
  • Author(s): Kusaka M, Kuroyanagi Y, Mori T, Nagaoka K, Sasaki H, Maruyama T, Hayakawa K, Shiroki R, Kurahashi H, Hoshinaga K
  • Journal Title: Cell Transplantation 18 Pages: 647-656
  • Peer Reviewed
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans. (2011)
  • 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 Genome
  • Place of Presentation: Steamboat Springs, Colorado, USA
• [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)
• [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
• [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
• [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
• [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
• [Presentation] Mutations of the SYCP3 gene in women with recurrent pregnancy loss (2009)
  • Author(s): Kurahashi H, Bolor H, Mori T, Nishiyama S, Inagaki H, Kogo H, Tsutsumi M, Ohye T
  • Organizer: European Society of Human Genetics conference 2009
  • Place of Presentation: Vienna, Austria
• [Presentation] Parental origin of de novo t(11 ; 22)(q23 ; q11) (2009)
  • Author(s): Kurahashi H, Inagaki H, Kato T, Ohye T, Kogo H, Shaikh TH, Emanuel BS
  • Organizer: 59th annual meeting of American Society of Human Genetics
  • Place of Presentation: Honolulu, Hawai, USA
• [Remarks]
  • URL: http://www.fujita-hu.ac.jp/~genome/mg/