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21世紀に入ってから急速に進展したゲノム解析技術は数多くの遺伝性疾患の原因を明らかにしてきましたが、その病態理解や治療法開発はまだ理解の途上にあります。遺伝子医療研究部門の目的は、特に発達障害を呈する遺伝性疾患を主たる対象として、ゲノム解析を基盤とする疾患原因を探索し、見出されたゲノム変化を糸口とした病態解析を行うことです。我々の最終的な目標は、遺伝性疾患におけるgenotype-phenotype-etiologyの連関を明らかにし、治療法開発に資することです。
Techniques of genetic analysis have drastically developed in the last two decades and have uncovered a number of causative genetic variants of genetic disorders, however their etiology or treatment have never been well understood. We, the Department of Genetics, aim to investigate the genetic cause using multiple genetic analyses and to identify an etiology of undiagnosed genetic disorders, especially those showing intellectual disability. Our goal is to establish a genotype-phenotype-etiology relationship in genetic disorders and contribute to development of therapy.
我々は、染色体分析・マイクロアレイ・次世代シークエンサーなどによるゲノム解析を手がかりに未診断の遺伝性疾患における疾患原因を明らかにしてきました。また、見出されたゲノム変化が転写産物や蛋白のレベルでどのような影響を及ぼし、病態を形成するかを解明し、生命現象の理解に寄与してきました。この目的のため、センター中央病院や他の医療機関と緊密に連携して症例の収集・解析に務めるほか、AMEDの未診断疾患の解析プロジェクトであるIRUDに参画し、データ解析に貢献してきました。
最近では、病態不明なゲノムバリアントの病的意義を明らかにするため、ゲノム編集技術であるi-GONAD法を用いて迅速かつ正確なマウスモデルの作製を行い、解析に供しています。これにより、従前の蛋白や細胞レベルでは明らかにならなかった、外表奇形や行動異常、中枢神経形成異常、てんかんへの感受性など、ゲノム変化と症状との連関がより直接的に示せるようになっています。これらの成果は国内外の学会で発表しているほか、論文を作成しています。
また、前身の遺伝学部において世界で初めて原因遺伝子ZEB2を同定したモワット・ウィルソン症候群 (Mowat-Wilson syndrome; MOWS)についても研究を継続しています。症例収集と解析を継続するほか、ZEB2の制御･被制御因子を探索して治療につながる知見を見出しています。また、遺伝子検査を持続的に行うことを目的として、当部門が衛生検査所の認定を取得し、検査会社（株）エスアールエルのご協力を得て、2023年7月から一般保険診療の枠組みによるZEB2の遺伝子解析受託を開始しました。
すでに論文化された成果については、トピックスならびに研究業績をご参照下さい。また、研究内容などについてはお気軽にお問い合わせください。連絡先は以下の通りです。
遺伝子医療研究部 部長 林 深（はやし・しん）
shin-hayashi@inst-hsc.jp
We have elucidated the causes of undiagnosed genetic disorders through genome analysis using chromosome analysis, microarrays, next-generation sequencings, and so on. We have also contributed to the understanding of biological phenomena by elucidating how the genomic variants affect the transcript or protein to determine the etiology. For the purpose, we have worked closely with the Center's Hospital and other medical institutions to recruit patients, and have contributed to data analysis by participating in IRUD, the project of the AMED to analyze undiagnosed diseases.
Recently, in order to determine the significance of genomic variants of unknown pathological significance, we have used the i-GONAD method, a genome editing technique, for rapid and precise generation of mouse models for analysis. This has allowed us to more directly demonstrate the correlation between genomic variants and phenotypes, such as dysmorphologies, aberrant behaviors, central nervous system dysplasia, and susceptibility to epilepsy, which were previously unclear at the protein or cellular level. These results have been presented at domestic and international conferences and publication have been prepared.
We are also continuing research on Mowat-Wilson syndrome (MOWS), for which we were the first in the world to identify the causative gene ZEB2 in the former Department of Genetics. In addition to continuing case collection and analysis, we are searching for regulating and regulated factors of ZEB2 and finding knowledge that may lead to treatment. In addition, to establish a sustainable system for genetic testing, our department obtained accreditation as a health laboratory, and with the cooperation of the testing company SRL, Inc., we began contracting genetic analysis of ZEB2 within general insurance treatment in July 2023.
Please refer to Topics and Research Achievements for the results of our research that have already been published. Please feel free to contact us for more information about our research. Our contact information is as follows.
Shin Hayashi, M.D., Ph.D.
Department Head of Genetics
shin-hayashi@inst-hsc.jp
・センター中央病院の上原朋子医師・大辻塩見医師が非常勤研究員として研究を開始しました。(2024/4)
・R3HDM1とそれに含まれるマイクロRNA (miRNA)の解析を契機として、山田主任研究員らがより効率よくmiRNAを細胞に導入する発現ベクターを発明し、特許申請しました。(2024/3)
・センター中央病院の医師らと臨床研究連携のコンソーシアムを立ち上げ、定期的な症例検討とディスカッションを開始しました。(2024/1)
・ZEB2の不完全なスプライシング異常がこれまでに報告のなかった軽症型モワット･ウィルソン症候群症例の原因となることを鈴木主任研究員らがミニジーン解析などにより証明して、Eur J Med Genet誌に論文報告しました。(2023/11)
・i-GONAD法によるマウスモデル作製･解析について、Yale University（ニューヘイブン、米国）において林部長が講演を行いました。(2023/11)
・i-GONAD法によるマウスモデル作製･解析について、American Society of Human Geneticsの年次大会（ワシントンDC, 米国）において林部長が口頭発表を行いました。(2023/11)
・衛生検査所の認定を取得し、検査会社（株）エスアールエルのご協力を得て、一般保険診療の枠組みによるZEB2の遺伝子解析受託を開始しました。(2023/7)
・i-GONAD法によるマウスモデル作製･解析について、Université de Roue（ルーアン、フランス）において林部長が講演を行いました。(2023/6)
・福士主任研究員（当時）らにより、2番染色体逆位を伴う軽度知的障害・自閉症様行動症例の解析を行い、その原因遺伝子がR3HDM1であることを世界で初めて示し、Am J Med Genet A誌に発表しました。(2021/5)
1 Suzuki Y, Nomura N, Yamada K, Yamada Y, Fukuda A, Hoshino K, Abe S, Kurosawa K, Inaba M, Mizuno S, Wakamatsu N, Hayashi S: Pathogenicity evaluation of variants of uncertain significance at exon-intron junction by splicing assay in patients with Mowat-Wilson syndrome. Eur J Med Genet. 66(12):104882, 2023.
1 Sugitate R, Muramatsu K, Ogata T, Goto M, Hayashi S, Sawaura N, Kawada-Nagashima M, Matsui A, Yamagata T: Recurrent pneumonia in three patients with MECP2 duplication syndrome with aspiration as the possible cause. Brain Dev 44(7): 486-491, 2022.
2 Tano S, Kotani T, Yoshihara M, Nakamura N, Matsuo S, Ushida T, Imai K, Itoh M, Oka Y, Sato E, Hayashi S, Ogi T, Kajiyama H: A case of non-immune hydrops fetalis with maternal mirror syndrome diagnosed by trio-based exome sequencing: An autopsy case report and literature review. Mol Genet Metab Rep 33:100925, 2022.
1 Fukushi D, Inaba M, Katoh K, Suzuki Y, Enokido Y, Nomura N, Tokita Y, Hayashi S, Mizuno S, Yamada K, Wakamatsu N: R3HDM1 haploinsufficiency is associated with mild intellectual disability. Am J Med Genet A 185(6):1776-1786, 2021.
2 若松延昭, 柴田克巳, 山田憲一郎：ビタミンB1 2.1.5 生化学・生理学（ヒトにおける消化・吸収）. 日本ビタミン学会（編集）ビタミン・バイオファクター総合事典. 朝倉書店, 115-118, 2021.
3 山田憲一郎, 林 深, 若松延昭：ZEB2（関連疾患：Mowat-Wilson症候群）. 小児科診療（小児遺伝子疾患辞典）. 診断と治療社, vol. 84, No.11, 1465-1467, 2021.
4 林 深, 水野誠司：CASK（関連疾患：小脳脳幹部低形成を伴う小頭症など）. 小児科診療（小児遺伝子疾患辞典）. 診断と治療社, vol. 84, No.11, 1469-1471, 2021.
1 山田裕一，山田憲一郎：Lesch-Nyhan症候群．特集「尿酸に影響する遺伝性代謝異常，最近の進展」，高尿酸血症と痛風 28: 22-27, 2020.
2 Katoh K, Aiba K, Fukushi D, Yoshimura J, Suzuki Y, Mitsui J, Morishita S, Tuji S, Yamada K, Wakamatsu N: Clinical and molecular genetic characterization of two female patients harboring the Xq27.3q28 deletion with different ratios of X chromosome inactivation. Hum Mutat 41: 1447-1460, 2020.
3 Matsukawa T, Yamamoto T, Honda A, Toya T, Ishiura H, Mitsui J, Tanaka M, Hao A, Shinohara A, Ogura M, Kataoka K, Seo S, Kumano K, Hosoi M, Narukawa K, Yasunaga M, Maki H, Ichikawa M, Nannya Y, Imai Y, Takahashi T, Takahashi Y, Nagasako Y, Yasaka K, Mano KK, Matsukawa MK, Miyagawa T, Hamada M, Sakuishi K, Hayashi T, Iwata A, Terao Y, Shimizu J, Goto J, Mori H, Kunimatsu A, Aoki S, Hayashi S, Nakamura F, Arai S, Momma K, Ogata K, Yoshida T, Abe O, Inazawa J, Toda T, Kurokawa M, Tsuji S: Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy. Brain Commun 2: fcz048, 2020.
1 山田裕一：最新文献紹介「種々のアミロイド前駆タンパク質mRNA (APP-mRNA)アイソフォームの定量化と、レッシュ・ナイハン病におけるエピスタシス（遺伝子間相互作用）」．高尿酸血症と痛風 27: 80, 2019.
2 Iwata S, Nakadai H, Fukushi D, Jose M, Nagahara M, Iwamoto T. Simple and large-scale chromosomal engineering of mouse zygotes via in vitro and in vivo electroporation. Sci Rep 9(1):14713, 2019.
1 大澤彦太，谷口敦夫，関田千恵子，金子裕隆，市川奈緒美，瀬戸洋平，山中 寿，山田裕一：HPRT1欠損症９例の遺伝子解析．痛風と核酸代謝42 (1)：123, 2018.
2 Fukushi D, Yamada K, Suzuki K, Inaba M, Nomura N, Suzuki Y, Katoh K, Mizuno S, Wakamatsu N: Clinical and genetic characterization of a patient with SOX5 haploinsufficiency caused by a de novo balanced reciprocal translocation. Gene 655:65-70, 2018.
1 Suzuki K, Yamada K, Fukuhara Y, Tsuji Y, Shibata K, Wakamatsu N: High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3-deficient mice. PLoS One 12:e0180279, 2017.
2 Fukushi D, Kurosawa K, Suzuki Y, Suzuki K, Yamada K, Watanabe S, Yokochi K, Wakamatsu N: Clinical and molecular genetic characterization of two siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter. Am J Med Genet A 173A(8): 2201-2209, 2017.
3 Suzuki Y, Enokido Y, Yamada K, Inaba M, Kuwata K, Hanada N, Morishita T, Mizuno S, Wakamatsu N: The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS). Oncotarget 8: 45470-45483, 2017.
4 Teraishi M, Takaishi M, Nakajima K, Ikeda M, Higashi Y, Shimoda S, Asada Y, Hijikata A, Ohara O, Hiraki Y, Mizuno S, Fukada T, Furukawa T, Wakamatsu N, Sano S. Critical involvement of ZEB2 in collagen fibrillogenesis: the molecular similarity between Mowat-Wilson syndrome and Ehlers-Danlos syndrome. Scientific Reports, 2017 Apr 19;7:46565. doi: 10.1038/srep46565.
5 Tanigawa J, Mimatsu H, Mizuno S, Okamoto N, Fukushi D, Tominaga K, Kidokoro H, Muramatsu Y, Nishi E, Nakamura S, Motooka D, Nomura N, Hayasaka K, Niihori T, Aoki Y, Nabatame S, Hayakawa M, Natsume J, Ozono K, Kinoshita T, Wakamatsu N, Murakami Y: Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties.Hum Mutat 38(7): 805-815, 2017.
6 山田裕一：核酸代謝異常症．日本臨牀別冊 新領域別症候群シリーズ No.37「精神医学症候群Ⅰ?その他の精神疾患を含めて?（第2版）」，日本臨牀社，pp. 177-182, 2017.
7 Ono H, Kurosawa K, Wakamatsu N, Masuda S :Hearing impairment in a female infant with interstitial deletion of 2q24.1q24.3.Ono H, Kurosawa K, Wakamatsu N, Masuda S: Hearing impairment in a female infant with interstitial deletion of 2q24.1q24.3. Congenit Anom (Kyoto) 57(4): 118-121, 2017.
1 山田裕一：先天性プリン代謝異常症．日本臨牀増刊号「高尿酸血症・低尿酸血症?最近の診断と治療?」, 日本臨牀社，74巻増刊号 9: 114-119, 2016.
2 Baba S, Saito T, Yamada Y, Takeshita E, Nomura N, Yamada K, Wakamatsu N, Sasaki M. Novel mutation in HPRT1 causing a splicing error with multiple variations. Nucleosides Nucleotides Nucleic Acids 36:1,1-6,2016.
1 松田安史，山田裕一，若松延昭，三澤美和，江川克哉，山内高弘，中村真希子，長谷川弘，市田公美，上田孝典：分子遺伝学的検査にて本邦初の変異と家族内発症が明らかになったLesch-Nyhan variantの一家系．痛風と核酸代謝 39(2): 121-128, 2015.
2 Takagi T, Nishizaki Y, Matsui F, Wakamatsu N, Higashi Y. De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome. Hum Mol Genet 24:6390-6402, 2015.
3 山田裕一： Lesch-Nyhan症候群（HPRT欠損症）．「今日の小児治療指針（第16版）」第６章 先天代謝異常，医学書院, pp 228-229, 2015
4 Yamada K, Aiba K, Kitaura Y, Kondo Y, Nomura N, Nakamura Y, Fukushi D, Murayama K, Shimomura Y, Pitt J, Yamaguchi S, Yokochi K, Wakamatsu N: Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion. J Med Genet 52: 691-698, 2015.
5 Hasegawa H, Shinohara Y, Nozaki S, Nakamura M, Oh K, Namiki O, Suzuki K, Nakahara A, Miyazawa M, Ishikawa K, Himeno T, Yoshida S, Ueda T, Yamada Y, Ichida K: Hydrophilic-interaction liquid chromatography tandem mass spectrometric determination of erythrocyte 5-phosphoribosyl 1-pyrophosphate in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency.J Chromatography B, 976-977: 55-60, 2015.
6 山田裕一：遺伝子変異診断．特集「痛風・核酸代謝における検査・診断法の進歩」，高尿酸血症と痛風 23 (1):30-36, 2015.
1 吉本武史，姫野隆洋，竹島慎一，音成秀一郎，山田憲一郎，山田裕一，栗山 勝：痙攣と精神運動遅滞を主訴としたhypoxanthine-guanine phosphoribosyltransferase 部分欠損症の一例. 臨床神経学 54: 892-896, 2014.
2 Yamada K, Naiki M, Hoshino S, Kitaura Y, Kondo Y, Nomura N, Kimura R, Fukushi D, Yamada Y, Shimozawa N, Yamaguchi S, Shimomura Y, Miura K, Wakamatsu N: Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis. Mol Genet Metab Rep 1: 455-460.
3 Suzuki Y, Jin C, Iwase T, Yazawa I: β-III Tubulin Fragments Inhibit α-Synuclein Accumulation in Models of Multiple System Atrophy. J Biol Chem 289:24374-24382.
4 Yamada Y, Nomura N, Yamada K, Kimura R, Fukushi D, Wakamatsu N, Matsuda Y, Yamauchi T, Ueda T, Hasegawa H, Nakamura M, Ichida K, Kaneko K, Fujimori S: Hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiencies: HPRT1 mutations in new Japanese families and PRPP concentration. Nucleosides Nucleotides Nucleic Acids 33: 218-222.
5 Kaneko K, Iwamoto H, Yasuda M, Inazawa K, Yamaoka N, Fukuuchi T, Tamura Y, Uchida S, Mawatari K, Nakagomi K, Yamada Y, Fujimori S: Proteomic analysis to examine the role of matrix proteins in a gouty tophus from a patient with recurrentgout. Nucleosides Nucleotides Nucleic Acids 33: 199-207.
6 山田裕一，若松延昭：HPRT欠損症（Lesch-Nyhan症候群、Kelley-Seegmiller症候群）．別冊日本臨床 新領域別症候群シリーズ No.28「神経症候群Ⅲ?その他の神経疾患を含めて?（第2版）」, pp 632-636, 2014.06.20.
7 若松延昭，平木洋子：Mowat-Wilson症候群．別冊日本臨床 新領域別症候群シリーズ No.29「神経症候群Ⅳ?その他の神経疾患を含めて?（第2版）」, pp 613-616, 2014.09.20.
8 Yamada Y, Nomura N, Yamada K, Matsuo M, Suzuki Y, Sameshima K, Kimura R, Yamamoto Y, Fukushi D, Fukuhara Y, Ishihara N, Nishi E, Imataka G, Suzumura H, Hamano S, Shimizu K, Iwakoshi M, Ohama K, Ohta A, Wakamoto H, Kajita M, Miura K, Yokochi K, Kosaki K, Kuroda T, Kosaki R, Hiraki Y, Saito K, Mizuno S, Kurosawa K, Okamoto N, Wakamatsu N: The Spectrum of ZEB2 Mutations Causing the Mowat-Wilson Syndrome in Japanese Populations. Am J Med Genet A: 164A(8):1899-1908.
9 Naiki M, Ochi N, Kato YS, Purevsuren J, Yamada K, Kimura R, Fukushi D, Hara S, Yamada Y, Kumagai T, Yamaguchi S, Wakamatsu N: Mutations in HADHB, which Encodes the β-subunit of Mitochondrial Trifunctional Protein, Cause Infantile Onset Hypoparathyroidism and Peripheral Polyneuropathy. Am J Med Genet A: 164A(5):1180-1187.
10 Fukushi D, Yamada K, Nomura N, Naiki M, Kimura R, Yamada Y, Kumagai T, Yamaguchi K, Miyake Y, Wakamatsu N: Clinical Characterization and Identification of Duplication Breakpoints in a Japanese Family with Xq28 Duplication Syndrome Including MECP2. Am J Med Genet A: 164A(4):924-933.
1 Fu R, Ceballos-Picot I, Torres RJ, Larovere LE, Yamada Y, Nguyen KV, Hegde M, Visser JE, Schretlen DJ, Nyhan WL, Puig JG, O’Neill PJ, Jinnah HA for the Lesch-Nyhan Disease International Study Group: Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain (2014) 137: 1282-1303, first published online August 22, 2013.
2 Yamada K, Takado Y, Kato YS, Yamada Y, Ishiguro H, Wakamatsu N: Characterization of the mutant β-subunit of β-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype. J Biochem 153: 111-119, 2013.
3 山田裕一，若松延昭：HPRT欠損症の原因となる新たなHPRT1遺伝子変異．痛風と核酸代謝37: 63, 2013
4 山田裕一：HPRT欠損症（Lesch-Nyhan症候群）．先天代謝異常ハンドブック（中山書店），Ⅱ各論, 12章プリン・ピリミジン代謝異常，遠藤文雄 編，pp 282-283, 2013.
5 山田裕一：HGPRTaseの遺伝子異常と女児例の発見．特集「日本が貢献した世界的新知見」，高尿酸血症と痛風 21 (1): 27-32, 2013.
6 山田裕一，若松延昭：遺伝病診療：HPRT欠損症診断．「核酸代謝の研究はいかに生命科学の発展に寄与したか」．痛風と核酸代謝36: 134, 2013.
7 山田裕一：先天性プリン代謝異常症に関わる２酵素 (HPRT, PRPPS)の遺伝子解析．痛風財団平成23年度研究助成に対する概要報告書 27: 8, 2013.
1 Yamada K, Nomura N, Yamano A, Yamada Y, Wakamatsu N. Identification and characterization of splicing variants of PLEKHA5 (Plekha5) during brain development. Gene 492: 270-275, 2012.
2 Naiki M, Mizuno S, Yamada K, Yamada Y, Kimura R, Oshiro M, Okamoto N, Makita Y, Seishima M, Wakamatsu N: MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet A, 158A: 97-102, 2012.
3 Fukushi D, Mizuno S, Yamada K, Kimura R, Yamada Y, Kumagai T, Wakamatsu N: Aneuploidy and intellectual disability. in Aneuploidy in Health and Disease, Storchova Z ed, InTech-Open Access Publisher (Rijeka, Croatia), pp 107-122, 2012.
4 山田裕一：PRPP合成酵素遺伝子PRPS1の遺伝子異常に起因する４つの症候群．痛風と核酸代謝36: 1-8, 2012.
5 山田裕一：ヒポキサンチン-グアニンホスホリボシルトランスフェラーゼ欠損症．別冊 日本臨床 新領域別症候群シリーズ No.19「先天代謝異常症候群（第２版）-病因・病態研究．診断治療の進歩-」（上），pp 573-583, 2012.
1 Mizuno S, Fukushi D, Kimura R, Yamada K, Yamada Y, Kumagai T, Wakamatsu N: Clinical and genomic characterization of sibling with a distal duplication of chromosome 9q [9q34.1-qter]. Am J Med Genet A, 155A: 2274-2280, 2011.
2 Mutoh N, Kitajima S, Ichihara S: Apoptotic cell death in the fission yeast Schizosacchamyces pombe indused by valprotid acid and its extreme susceptibility to pH change. Biosci Biotechnol Biochem 75: 1113-1118, 2011.
3 Kaneko K, Yoshida N, Okazaki K, Yamanobe T, Hachisu H, Yamaoka N, Yasuda M, Ogata N, Yamada Y, Uchida S, Fujimori S: Urinary stone analysis in a patient with hyperuricemia to determine the mechanism of stone formation. Nucleosides Nucleotides Nucleic Acids 30: 1072-1076, 2011.
4 Yamada Y, Wakamatsu N, Taniguchi A, Kaneko K, Fujimori S: Hypoxanthine guanine phosphoribosyltransferase (HPRT) mutations in Asian population. Nucleosides Nucleotides Nucleic Acids 30: 1248-1255, 2011.
5 Yamaoka N, Inazawa K, Inagawa S, Fujimori S, Yasuda M, Mawatari K, Nakagomi K, Yamada Y, Kaneko K: Simultaneous determination of purine and pyrimidine metabolites in HPRT-deficient cell lines. Nucleosides Nucleotides Nucleic Acids 30: 1256-1259, 2011.
6 Taniguchi1 A, Yamada Y, Hakota M, Sekita C, Kawamoto M, Kaneko H, Yamanaka H: Molecular characterization of deletion in the HPRT gene in a patient with Lesch-Nyhan syndrome. Nucleosides Nucleotides Nucleic Acids 30: 1266-1271, 2011.
7 Yamada Y, Yamada K, Nomura N, Yamano A, Kimura R, Naiki M, Fukushi D, Wakamatsu N, Taniguchi A, Kaneko K, Fujimori S: Molecular analysis of X-linked inborn errors of purine metabolism: HPRT1 and PRPS1 mutations. Nucleosides Nucleotides Nucleic Acids 30: 1272-1275, 2011.
1 Yamada Y, Yamada K, Nomura N, Yamano A, Kimura R, Tomida S, Naiki M, Wakamatsu N: Molecular analysis of two enzyme genes, HPRT1 and PRPS1, causing X-linked inborn errors of purine metabolism. Nucleosides Nucleotides Nucleic Acids 29: 291-294, 2010.
2 Yamaoka N, Kaneko K, Kudo Y, Aoki M, Yasuda M, Mawatari K, Nakagomi K, Yamada Y, Yamamoto T: Analysis of purine in purine-rich cauliflower. Nucleosides Nucleotides Nucleic Acids 29: 518-521, 2010.
3 Yamada K, Fukushi D, Ono T, Kondo Y, Kimura R, Nomura N, Kosaki K, Yamada Y, Mizuno S, Wakamatsu N: Characterization of a de novo balanced t(4;20)(q33;q12) translocation in a patient with mental retardation. Am J Med Genet A, 152A: 3057-3057, 2010.
4 Yamada K, Miura K, Hara K, Suzuki M, Nakanishi K, Kumagai T, Ishihara N, Yamada Y, Kuwano R, Tsuji S, Wakamatsu N: A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations. BMC Medical Genetics 11:171, doi:10.1186/1471-2350-11-171, 2010.
5 山田裕一：核酸代謝異常（Lesch-Nyhan症候群など）．小児科診療-増刊号「特集小児の治療指針」，73 (suppl): 520-522, 2010.
1 Lyle R, Bena F1, Gagos S, Gehrig C, Lopez G, Schinzel A, Lespinasse J, Bottani A, Dahoun S, Taine L3, Doco-Fenzy M, Cornillet-Lefebvre P, Pelet A, Lyonnet S, Toutain A, Colleaux L, Horst J, Kennerknecht I, Wakamatsu N, Descartes M, Franklin JC, Florentin-Arar L, Kitsiou S, Ait Yahya-Graison E, Costantine M, Sinet PM, Delabar JM, Antonarakis SE: Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur J Hum Genet 17: 454-466, 2009
2 Garavelli L, Zollino M, Cerruti Mainardi P, Gurrieri F, Rivieri F, Soli F, Verri R, Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli P, Forzano F, Seri M, Wischmeijer A, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti E, Bergamaschi R, De Brasi D, Sperandeo MP, Mari F, Uliana V, Mostardini R, Cecconi M, Grasso M, Sassi S, Sebastio G, Renieri A, Silengo M, Bernasconi S, Wakamatsu N, Neri G: Mowat-Wilson syndrome: facial phenotype changing with age. Study of 19 Italian patients and review of the others literature. Am J Med Genet 149A: 417-426, 2009.
3 Fukushi D, Watanabe N, Kasai F, Haruta M, Kikuchi A, Kikuta A, Kato K,Nakadate H, Tsunematsu Y, Kaneko Y: Centrosome amplification is correlated with ploidy divergence, but not with MYCN amplification, in neuroblastomatumors. Cancer Genet Cytogenet 188:32-41, 2009
4 山田裕一：HPRT欠損症．「特集:高尿酸血症・痛風Update」．日本臨牀66: 687-693, 2008.
5 Yamada Y, Nomura N, Yamada K, Wakamatsu N, Kaneko K, Fujimori: Molecular analysis of HPRT deficiencies: novel mutations and the spectrum of Japanese mutations. Nucleosides Nucleotides Nucleic Acids 27: 570-574, 2008.
6 Ishida Y, Ishimaru A, Tauchi H, Yamaguchi A, Yokoyama M, Hiroi K, Wakamatsu N, Yamada Y : Partial hypoxanthine-guanine phosphoribosyltransferase deficiency due to a newly recognized mutation presenting with renal failure in a one-year-old boy. Eur J Pediatr 167: 957-959, 2008.
7 Mutoh N, Kitajima S: Accelerated chronological aging of a mutant fission yeast deficient in both glutathione and superoxide dismutase having Cu and Zn as cofactors and its enhancement by Sir2 deficiency. Biosci Biotech Biochem 71: 2841-2844, 2007.
8 山田裕一，野村紀子，若松延昭：HPRT欠損症の遺伝子解析：新たな６変異とアジア人変異の総括．痛風と核酸代謝 31: 31-40, 2007.
9 小野教夫，木村礼子，山田憲一郎，若松延昭：見えない染色体異常 -染色体構築と分配機構の異常による先天性疾患．実験医学 25: 776-781, 2007.
10 Yamada Y, Nomura N, Yamada K, Wakamatsu N: Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations. Mol Genet Metab 90: 70-76, 2007.
11 Kimura R, Takeshima K, Mizuno S, Kosaki K, Machida J, Kamamoto M, Muro Y, Shimosato K, Wakamatsu N, Sonta S, OnoT: Monopolar preparation of human lymphocytes for evaluation of the metaphase chromosome alignment. Chromosome Science 9: 75-83, 2006.
12 Ono T: Key roles of condensins in mitotic chromosome assembly and segregation. Chromosome Science 9: 33-45, 2006.
13 Yamada Y, Wakamatsu N: Molecular analysis of hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency. Genetic Errors Associated with Purine and Pyrimidine Metabolism in Humans: Diagnosis and Treatment, Moriwaki Y ed, Research Signpost, Kerala, pp 15-27, 2006.
14 Kondo Y, Mizuno S, Ohara K, Nakamura T, Yamada K, Yamamori S, Hayakawa C, Ishii T, Yamada Y, Wakamatsu N: Two cases of partial trisomy 21 (pter-q22.1) without the major features of Down syndrome. Am J Med Genet 140A: 227-232. 2006.
15 Mutoh N, Kawabata M, Kitajima S: Effects offour oxidants, menadione, 1-chloro-2,4-dinitrobenzene, hydrogen peroxide and cumene hydroperoxide, on fission yeastSchizosaccharmoyces pombe. J Biochem 138: 797-804, 2005. 16 Ishihara N, Shimada A, Kato J, Niimi N, Tanaka S, Miura K, Suzuki T, Wakamatsu N, Nagaya M: Variations in aganglionic segment length of the enteric neural plexus in Mowat-Wilson syndrome. J Pediatr Surg 40:1411-1419, 2005.
17 Mizuno S, Yamada Y, Yamada K, Nomura N, Wakamatsu N: Clinical variability in a Japanese hereditary lymphedema type I family with an FLT4 mutation. Cong Anom 45: 59-61, 2005.
18 Mutoh N, Kawabata M, Nakagawa CW, Kitajima S: Pro-oxidant action of phloxine B on fission yeast Schizosaccharomyces pombe. Yeast 22: 91-97, 2005.
19 Ono T, Fang Y, Spector DL, Hirano T: Spatial and temporal regulation of condensins I and II in mitotic chromosome assembly in human cells. Mol Biol Cell 15: 3296-3308, 2004.
20 Yamada Y, Yamada K, Sonta S, Wakamatsu N, Ogasawara N: Mutations in the hypoxanthine guanine phosphoribosyltransferase gene (HPRT1) in Asian HPRT deficient families. Nucleosides Nucleotides Nucleic Acids 23: 1169-1172, 2004.
21 Mizunuma M, Yamada Y, Yamada K, Sonta S, Wakamatsu N, Kaneko K, Ogasawara N, Fujimori S: Disruption in the hypoxanthine phosphoribosyltransferase gene caused by translocation in a patient with Lesch-Nyhan syndrome. Nucleosides Nucleotides Nucleic Acids 23: 1173-1176, 2004.
22 Ishihara N, Yamada K, Yamada Y, Miura K, Kato J, Kuwabara N, Hara Y, Kobayashi Y, Hoshino K, Nomura Y, Mimaki M, Ohya K, Matsushima M, Nitta H, Tanaka K, Segawa M, Ohki T, Ezoe T, Kumagai T, Onuma A, Kuroda T, Yoneda M, Yamanaka T, Saeki M, Segawa M, T Saji, Nagaya M, WakamatsuN: Clinicaland molecular analysis of Mowat-Wilson syndrome associated with ZFHX1Bmutations and deletions at 2q22-q24.1. J Med Genet 41: 387-394, 2004.
23 Silengo M, Ferrero GB, Wakamatsu N: Pachygyria and cerebellar hypoplasia in a patient with a 2q22-q23 deletion that includes the ZFHX1B gene. Am J Med Genet 127A: 109, 2004
24 Ono T, Losada A, Hirano M, Myers MP, Neuwald AF, Hirano T: Differential contributions of condensin I and condensin II to mitotic chromosome architecture in vertebrate cells. Cell 115: 109-121, 2003.
25 Nagaya M, Kato J, Niimi, N, Tanaka S, Wakamatsu N: Clinical feature of a form of Hirschspurung’s disease caused by a novel genetic abnormality. J Pediar Surg 37: 1117-1122, 2002.
26 Mutoh N, Nakagawa CW, Yamada K: Characterization of Cu, Zn superoxide dismutase deficient mutant of fission yeast Schizosaccharomyces pombe. Curr Genet 41: 82-88, 2002
27 Yoneda M, Fujita T, Yamada Y, Yamada K, Fujii A, Inagaki T, Nakagawa H, Kishikawa M, Shimada A, Nagaya M, Azuma T, Kuriyama M, Wakamatsu N: Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B. Neurology 59: 1637-1640, 2002.
28 Isoai A, Kimura H, Reichert A, Schorgendorfer K, Nikaido K, Tohda H, Giga-Hama Y, Mutoh N, Kumagai H: Production of D-amino acid oxidase (DAO) of Trigonopsis variabilis in Schizosaccharomyces pombe, and the characterization of biocatalysts prepared with recombinant cells. Biotechnol Bioeng 80: 22-32, 2002.
29 Yamada H, Adachi T, Fukatsu A, Misao S, Yamada Y, Aoki T, Miura N, Sakuma M, Nishikawa K, Futenma A, Kakumu S: Extracellular superoxide dismutase and glomerular cells: its production and regulation. FEBS Lett 519: 77-81, 2002.
30 Yamada K, Yamada Y, Nomura N, Miura K, Wakako R, Hayakawa C, Matsumoto A, Kumagai T, Yoshimura I, Miyazaki S, Kato K, Sonta S, Ono H, Yamanaka T, Nagaya M, Wakamatsu N: Nonsense and frameshift mutations in ZFHX1B, encoding Smad-Interacting protein 1, cause a complex developmental disorder with a great variety of clinical features. Am J Hum Genet 69: 1178-1185, 2001.
31 Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H, Kitoh H, Mutoh N, Yamanaka T1, Mushiake K, Kato K, Sonta S, Nagaya M: Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet 27: 369-370, 2001.
32 Ono T, Kondoh Y, Kagiyama N, Sonta S, Yoshida MC: Genomic organization and chromosomal distribution of rat ID elements. Genes Genet Syst 76: 213-220, 2001.
33 Ono T, Sonta S: Chromosome map of cosmid clones constructed with Chinese hamster genomic DNA. Cytogenet Cell Genet 95: 97-102, 2001.
34 Machida J, Yamada Y, Ogasawara N, Kaetsu A, Yamamoto T: Lesch-Nyhan syndrome: Case report and genetic study of one Japanese family. Asian J Oral Maxillofac Surg 13: 111-115, 2001.
35 Yamada Y, Miura K, Kumagai T, Hayakawa C, Miyazaki S, Matsumoto A, Kurosawa K, Nomura N, Taniguchi H, Sonta S, Yamanaka T, Wakamatsu N: Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation. Hum Mutat (Online#443) 18: 253, 2001.
