Pathophysilogy of brain dysfunction in Angelman and Prader-Willi syndrome.

• Project/Area Number: 21591306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nagoya City University (2011); Hokkaido University (2009-2010)
• Principal Investigator: SAITOH Shinji 名古屋市立大学, 大学院・医学研究科, 教授 (00281824)
• Co-Investigator(Kenkyū-buntansha): SHIRAISHI Hideaki 北海道大学, 北海道大学病院, 助教 (80374411)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 小児神経学 / Angelmen症候群 / Prader-Willi症候群 / 精神遅滞 / てんかん / 脳磁図 / ゲノム刷り込み現象

Research Abstract

To uncover the pathophysiology underlying brain dysfunction in Angelman syndrome(AS) and Prader-Willi syndrome(PWS), we performed comprehensive genetic analyses on 168 patients with AS and 202 patients with PWS. We identified causative molecular abnormalities in 54 patients(32.1%) for AS and 82 patients(40.6%) for PWS. Furthermore, we identified one patients with a SLC9A6 mutation 2 patients with submicroscopic chromosomal rearrangements in AS, and 22 patients with submicroscopic chromosomal rearrangements in PWS. These underlying molecular abnormalities should indicate common pathway to cause brain dysfunction in AS and in PWS.

Research Products

• [Journal Article] A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome (2011)
  • Author(s): Takahashi Y, Hosoki K, Matsushita M, Funatsuka M, Saito K, Kanazawa H, Goto Y-i, Saitoh S
  • Journal Title: Am J Med Genet Part B : Neuropsychiatric Genetics Volume: 156 Issue: 7 Pages: 799-807
  • DOI: 10.1002/ajmg.b.31221
  • Peer Reviewed
• [Journal Article] West Syndrome Associated with Mosaic Duplication of FOXG1 in a Patient with Maternal Uniparental Disomy of Chromosome 14 (2011)
  • Author(s): Tohyama J, Yamamoto T, Hosoki K, Nagasaki K, Akasaka N, Ohashi T, Kobayashi Y, Saitoh S
  • Journal Title: Am J Med Genet Part A Volume: 155 Issue: 10 Pages: 2584-2588
  • DOI: 10.1002/ajmg.a.34224
  • Peer Reviewed
• [Journal Article] Direct correlation between the facial nerve nucleus and hemi-facial seizures associated with a gangliocytoma of the floor of the fourth ventricle : a case report (2011)
  • Author(s): Yagyu K, Sueda K, Shiraishi H, Asahina N, Sakurai K, Kohsaka S, Sawamura Y, Saitoh S
  • Journal Title: Epilepsia Volume: 52 Issue: 12 Pages: 204-6
  • DOI: 10.1111/j.1528-1167.2011.03299.x
  • Peer Reviewed
• [Journal Article] Comparison of three methods for localizing interictal epileptiform discharges with magnetoencephalography (2011)
  • Author(s): Shiraishi H, Ahlfors SP, Stufflebeam SM, Knake S, Larsson PG, Hamalainen MS, Takano K, Okajima M, Hatanaka K, Saitoh S, Dale AM, Halgren E
  • Journal Title: J Clin Neurophysiol Volume: 28 Issue: 5 Pages: 431-40
  • DOI: 10.1097/wnp.0b013e318231c86f
  • Peer Reviewed
• [Journal Article] Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies (2011)
  • Author(s): Hayashi S, Imoto I, Aizu Y, Okamoto N, Mizuno S, Kurosawa K, Okamoto N, Honda S, Araki S, Mizutani S, Numabe H, Saitoh S, Kosho T, Fukushima Y, Mitsubuchi H, Endo F, Chinen Y, Kosaki R, Okuyama T, Ohki H, Yoshihashi H, Ono M, Takada F, Ono H, Yagi M, Matsumoto H, Makita Y, Hata A, Inazawa J
  • Journal Title: J Hum Genet Volume: 56 Issue: 2 Pages: 110-124
  • DOI: 10.1038/jhg.2010.129
• [Journal Article] Genetic analysis of two Japanese families with progressive external ophthalmoplegia and parkinsonism (2011)
  • Author(s): Sato K., et al
  • Journal Title: J Neurol Volume: 258 Pages: 1327-1332
  • Peer Reviewed
• [Journal Article] Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay (2011)
  • Author(s): Saitsu H., et al
  • Journal Title: Am J Med Genet Part B : Neuropsychiatric Genetics Volume: 156 Pages: 799-807
  • Peer Reviewed
• [Journal Article] Comparison of three methods for localizing interictal epileptiform discharges with raagnetoencephalography (2011)
  • Author(s): Shiraishi H., et al
  • Journal Title: J Clin Neurophysiol Volume: 128 Pages: 431-440
  • Peer Reviewed
• [Journal Article] MEG time-frequency analyses for pre and post surgical evaluation of patients with epileptic rhythmic fast activity (2010)
  • Author(s): Sueda K, Takeuchi F, Shiraishi H, Nakane S, Asahina N, Kohsaka S, Nakama H, Otsuki T, Sawamura Y, Saitoh S
  • Journal Title: Epilepsy Res Volume: 88 Issue: 2-3 Pages: 100-107
  • DOI: 10.1016/j.eplepsyres.2009.10.002
  • NAID: 120002015023
• [Journal Article] The applications of time-frequency analyses to ictal magnetoencephalography in neocortical epilepsy (2010)
  • Author(s): Yagyu K, Takeuchi F, Shiraishi H, Nakane S, Sueda K, Asahina N, Kohsaka S, Umeoka S, Usui N, Baba K, Saitoh S
  • Journal Title: Epilepsy Res Volume: 90 Issue: 3 Pages: 199-206
  • DOI: 10.1016/j.eplepsyres.2010.05.001
  • NAID: 120002383268
• [Journal Article] Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay (2010)
  • Author(s): Saitsu H, Tohyama J, Kumada T, Egawa K, Hamada K, Okada I, Mizuguchi T, Osaka H, Miyata R, Furukawa T, Haginoya K, Hoshino H, Goto T, Hachiya Y, Yamagata T, Saitoh S, Nagai T, Nishiyama K, Nishimura A, Miyake N, Komada M, Hayashi K, Hirai SI, Ogata K, Kato M, Fukuda A, Matsumoto N
  • Journal Title: Am J Hum Genet Volume: 86 Issue: 6 Pages: 881-891
  • DOI: 10.1016/j.ajhg.2010.04.013
  • Peer Reviewed
• [Journal Article] Parthenogenetic chimaerism/mosaicism with a Silver-Russell syndrome-like phenotype (2010)
  • Author(s): Yamazawa K, Nakabayashi K, Kagami M, Sato T, Saitoh S, Horikawa R, Hizuka N, Ogata T
  • Journal Title: J Med Genet Volume: 47 Issue: 11 Pages: 782-785
  • DOI: 10.1136/jmg.2010.079343
• [Journal Article] MEG time-frequency analyses for pre and post surgical evaluation of patients with epileptic rhythmic fast activity. (2010)
  • Author(s): Sueda K., et al.
  • Journal Title: Epilepsy Res Volume: 88 Pages: 100-107
  • Peer Reviewed
• [Journal Article] The applications of time-frequency analyses to ictal magnetoencephalo graphy in neocortical epilepsy. (2010)
  • Author(s): Yagyu K., et al.
  • Journal Title: Epilepsy Res Volume: 90 Pages: 199-206
  • Peer Reviewed
• [Journal Article] MERRF/MELAS overlap syndrome : A double pathogenic mutation in mitochondrial tRNA genes. (2010)
  • Author(s): Nakamura M., et al.
  • Journal Title: J Med Genet Volume: 47 Pages: 659-664
  • Peer Reviewed
• [Journal Article] Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and devel opmental delay. (2010)
  • Author(s): Saitsu H., et al.
  • Journal Title: Am J Med Genet Volume: 86 Pages: 881-891
  • Peer Reviewed
• [Journal Article] Parthenogenetic chimaerism/mosaicism with a Silver-Russell syndrome-like phenotype. (2010)
  • Author(s): Yamazawa K., et al.
  • Journal Title: J Med Genet Volume: 47 Pages: 782-785
  • Peer Reviewed
• [Journal Article] Maternal uniparental disomy 14 syndrome demonstrates Prader-Willi syndrome-like phenotype (2009)
  • Author(s): Hosoki K, Kagami M, Tanaka T, Kubota M, Kurosawa K, Kato M, Uetake K, Tohyama J, Ogata T, Saitoh S
  • Journal Title: J Pediatr Volume: 155 Issue: 6 Pages: 900-903
  • DOI: 10.1016/j.jpeds.2009.06.045
• [Journal Article] Maternal uniparental disomy 14 syndrome demonstrates Prader-Willi syndrome-like phenotype (2009)
  • Author(s): Hosoki K., et al.
  • Journal Title: Journal of Pediatrics 155 Pages: 900-903
  • Peer Reviewed
• [Journal Article] A de novo direct duplication of 16q22.1→q23.1 in a boy with midface hypoplasia and mental retardation (2009)
  • Author(s): Tokutomi T., et al.
  • Journal Title: Am J Med Genet A 149A Pages: 2560-2563
  • Peer Reviewed
• [Journal Article] Mutations of FHL1 gene cause Emery-Dreifuss muscular dystrophy (2009)
  • Author(s): Gueneau L., et al.
  • Journal Title: Am J Hum Genet 85 Pages: 338-353
  • Peer Reviewed
• [Journal Article] Hand-foot-genital syndrome with a 7p15 deletion demonstrates a clinically recognizable syndrome
  • Author(s): Hosoki K, Ohta T, Fujita K, Nishigaki S, Shiomi M, Niikawa N, Saitoh S
  • Journal Title: Pediatr Int Volume: (in press)
• [Journal Article] Clinical Phenotype and Candidate Genes for the 5q31.3 Microdeletion Syndrome
  • Author(s): Hosoki K, Ohta T, Natsume J, Imai S, Okumura A, Matsui T, Harada N, Bacino CA, Scaglia F, Jones JY, Niikawa N, Saitoh S
  • Journal Title: Am J Med Genet A Volume: (in press)
• [Presentation] PWS様表現型を示す微細染色体異常 (2011)
  • Author(s): 細木華奈、太田亨、新川詔夫、齋藤伸治
  • Organizer: 第56回日本人類遺伝学会
  • Place of Presentation: 幕張
  • Year and Date: 2011-11-10
• [Presentation] PWS様表現型を示す微細染色体異常 (2011)
  • Author(s): 細木華奈, 等
  • Organizer: 第56回日本人類遺伝学会
  • Place of Presentation: 幕張メッセ(千葉県)
  • Year and Date: 2011-11-10
• [Presentation] 5q31.3 microdeletion syndrome is a clinically discernible new syndrome characterized by severe neonatal hypotonia, feeding difficulties, respiratory distress, and severe developmental delay (2011)
  • Author(s): HOSOKI K, OHTA T, NATSUME J, IMAI S, OKUMURA A, MATSUI T, HARADA N, SCAGLIA F, BACINO CA, NIIKAWA N, SAITOH S
  • Organizer: 61th Annual Meeting of American Society of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2011-10-14
• [Presentation] 5q31.3 microdeletion syndrome is a clinically discernible new syndrome characterized by severe neonatal hypotonia, feeding difficulties, respiratory distress, and severe developmental delay (2011)
  • Author(s): Hosoki K., et al
  • Organizer: 61st Annual Meeting of American Society of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2011-10-14
• [Presentation] 5q31微細欠失は乳児期の筋緊張低下と重度精神遅滞を示す新しい症候群である (2011)
  • Author(s): 齋藤伸治、細木華奈、夏目淳、今井純好、中島翠、植田佑樹、朝比奈直子、白石秀明
  • Organizer: 第53回日本小児神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-26
• [Presentation] Prader-Willi症候群の摂食の改善について (2011)
  • Author(s): 高野亨子、小沢浩、稲田穣、上石晶子、有本潔、木実谷哲史、久保田雅也、齋藤伸治
  • Organizer: 第53回日本小児神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-26
• [Presentation] 5q31微細欠失は乳児期の筋緊張低下と重度精神遅滞を示す新しい症候群である (2011)
  • Author(s): 齋藤伸治, 等
  • Organizer: 第53回日本小児神経学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-05-26
• [Presentation] Prader-Willi症候群の摂食の改善について (2011)
  • Author(s): 高野亨子, 等
  • Organizer: 第53回日本小児神経学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-05-26
• [Presentation] ゲノム刷り込み関連疾患Prader-Willi症候群の表現型を規定する遺伝学的因子の検討 (2010)
  • Author(s): 細木華奈、太田亨、新川詔夫、齋藤伸治
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Submicroscopic chromosomal rearrangements in patients with a Prader-Willi syndrome-like phenotype. (2010)
  • Author(s): Hosoki K., et al.
  • Organizer: 60th Annual Meeting of American Society of Human Genetics
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2010-11-05
• [Presentation] PWS様表現型を示す微細染色体異常 (2010)
  • Author(s): 細木華奈、太田亨、新川詔夫、齋藤伸治
  • Organizer: 第55回日本人類遺伝学会
  • Place of Presentation: さいたま
  • Year and Date: 2010-10-28
• [Presentation] 脳磁図棘波の形態解析は限局性皮質形成異常の診断に有用である (2010)
  • Author(s): 植田佑樹, 等
  • Organizer: 第44回日本てんかん学会
  • Place of Presentation: 岡山
  • Year and Date: 2010-10-15
• [Presentation] 微細染色体異常はプラダー・ウィリー症候群の重要な鑑別診断である (2010)
  • Author(s): 齋藤伸治、高橋有美、植田佑樹、伊藤智城、白石秀明
  • Organizer: 第52回日本小児神経学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2010-05-20
• [Presentation] 磁図計測を用いた皮質形成異常の早期診断 (2010)
  • Author(s): 白石秀明、植田佑樹、伊藤智城、高橋有美、香坂忍、齋藤伸治
  • Organizer: 第113回日本小児科学会総会
  • Place of Presentation: 盛岡
  • Year and Date: 2010-04-23
• [Presentation] 脳磁図計測を用いた皮質形成異常の早期診断 (2010)
  • Author(s): 白石秀明, 等
  • Organizer: 第113回日本小児科学会学術集会
  • Place of Presentation: 盛岡
• [Presentation] 微細染色体異常はプラダー・ウィリー症候群の重要な鑑別診断である (2010)
  • Author(s): 斉藤伸治, 等
  • Organizer: 第52回日本不児神経学会総会
  • Place of Presentation: 福岡
• [Presentation] A novel SLC9A6 gene mutation in a Japanese patient resembling Angelman syndrome (2009)
  • Author(s): Takahashi Y, Funatsuka M, Saitoh K, Hosoki K, Ueda Y, Itoh T, Yagyu K, Shiraishi H, Saitoh S
  • Organizer: 59th Annual Meeting of American Society of Human Genetics
  • Place of Presentation: Honolulu, USA
  • Year and Date: 2009-10-23
• [Presentation] プラダー・ウィリー症候群様表現型を呈した微細染色体異常 (2009)
  • Author(s): 細木華奈、太田亨、沼部博直、高田史男、塩見正司、新川詔夫、齋藤伸治
  • Organizer: 第54回日本人類遺伝学会
  • Place of Presentation: 東京
  • Year and Date: 2009-09-25
• [Presentation] 日本人Angelman症候群の分子遺伝学的および臨床的解析 (2009)
  • Author(s): 細木華奈、齋藤伸治
  • Organizer: 第16回遺伝子診療学会
  • Place of Presentation: 札幌
  • Year and Date: 2009-07-31
• [Presentation] SLC9A6変異はアンジェルマン症候群の表現型を示すX連鎖精神遅滞である (2009)
  • Author(s): 高橋有美、斎藤加代子、伊藤智城、柳生一自、朝比奈直子、白石秀明、齋藤伸治
  • Organizer: 第51回日本小児神経学会総会
  • Place of Presentation: 米子
  • Year and Date: 2009-05-28
• [Presentation] A novel SLC9A6 gene mutation in a Japanese patient resembling Angelman syndrome. (2009)
  • Author(s): Takahashi Y., et al.
  • Organizer: 59th Annual Meeting of American Society of Human Genetics
  • Place of Presentation: Honolulu, USA
• [Book] 診断手順と技法、Prader-Willi症候群の基礎と臨床 (2011)
  • Author(s): 齋藤伸治、永井敏郎
  • Publisher: 診断と治療社
• [Book] Angelman症候群の運動発達、小児科臨床ピクシス19ここまでわかった小児の発達 (2010)
  • Author(s): 齋藤伸治、五十嵐隆
  • Publisher: 中山書店