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遺伝子医療研究部門の目的は、主に知的障害・発達障害・多発奇形・てんかんなどゲノム変異が原因であると考えられる先天異常疾患を主な対象として、その発症機序を明らかにすることです。この目的のため、中央病院をはじめとした国内外の医療機関と連携して症例を収集し、細胞遺伝学・分子生物学・生化学・神経科学的手法などを用いて病態の解明を行い、治療や療育につながる知見を得て臨床へ還元しています。
We, Department of Genetics, are aiming to clarify an etiology of congenital disorders which may be caused by genetic aberrations, e.g. intellectual disability, developmental delay, multiple dysmorphologies, or syndromic epilepsy. We have collaborated with the Central Hospital and other domestic/international medical institutes to recruit patients, and shed light on their etiology using techniques of cytogenetics, molecular biology, biochemistry and neuroscience to obtain an experimental evidence contributing to treatment, or rehabilitation of the patients.
遺伝子医療研究部門では、前身の遺伝学部において2001年にコロニー中央病院で加療するモワット・ウィルソン症候群の症例の解析から、SIP1というタンパク質をコードするZEB2遺伝子が本症候群の病因遺伝子であることを世界で初めて明らかにし、論文発表しました[Wakamatsu et al. Nat Genet. 2001]。それ以来、国内外で本症候群と疑われた170例以上のZEB2遺伝子解析を行ってきました。2014年には、当部門で本症候群と確定診断した国内の40症例について、人口当たりの病気の出現頻度や症状の種類、ZEB2遺伝子変異の種類と病気の症状との相関をまとめた論文を発表しました。これらの研究成果をもとに、2015年に本症候群は厚生労働省の指定難病に認定されました。現在、患者やご家族、医療従事者向けに、本症候群に関する詳しい情報が難病情報センターのホームページで公開されています（指定難病178、モワット・ウィルソン症候群；http://www.nanbyou.or.jp/entry/4595）
その他、センター（旧コロニー）中央病院や他の医療機関との共同研究として以下の研究を行っています。
１．原因不明の基底核疾患の症例を解析し、SLC19A3、HIBCH、ECHS1の3つの病因遺伝子を同定しました。[Yamada K et al. BMC Med Genet. 2010; Yamada K et al. Mol Genet Metab Rep. 2014; Yamada K et al. J Med Genet. 2015]。現在、国内の病因不明の基底核疾患の症例について、SLC19A3とECHS1遺伝子の解析を行う体制を整えています。
２．過成長症候群のひとつであるPIK3CA-related overgrowth spectrum (PROS)の診断方法の開発と治療方法の検討を行いました。PI3K/AKT/mTOR経路の抑制を指標に治療薬の検討を行った結果、メトホルミンは、PI3K/AKT/mTOR経路の抑制効果があり、なおかつ正常細胞への影響が少ないため治療薬として有望であることを明らかにしました [Suzuki et al. Oncotarget. 2017]。
３．軽度知的障害と自閉症が見られ、de novoの染色体相互転座を伴う症例の転座断点部位の解析を行った結果、断点部位をSOX5遺伝子の中に同定し、本邦初のLamb-Shaffer症候群として誌上に発表しました [Fukushi et al. Gene. 2018]。
４. de novoの2番染色体逆位を伴い、軽度知的障害と自閉症に似た行動を示す新規の症例について、逆位の断点部位を解析した結果、R3HDM1を知的障害の新規病因遺伝子として同定し、この症例を世界初のR3HDM1欠損症として誌上に発表しました[Fukushi et al. Am J Med Genet A. 2021]。
５．Xq27.3q28領域のほぼ同じ領域に欠失があるが臨床症状の異なる女児2例の解析を行い、重症度とX染色体不活性化が相関していることを示しました。さらにHi-Cデーターベースを用いたクロマチン高次構造 (topologically associating domains, TADs) 解析を行い、欠失によりTADsの融合が起こり、欠失周辺領域の遺伝子発現が変化する可能性を示しました。[Katoh et al. Hum Mutat. 2020]。
なお、これらの疾患については現在も症例の収集・解析を継続しております。モワット･ウィルソン症候群やSLC19A3変異が疑われる症例につきましては是非ご相談下さい。連絡先は以下の通りです。
shin-hayashi@inst-hsc.jp 林 深（はやし・しん）
We identified ZEB2 as a causative gene of Mowat-Wilson syndrome (MOWS) for the first time in the world by analysis of a MOWS patient with a balanced chromosomal translocation [Wakamatsu et al. Nat Genet. 2001]. Thereafter, we have recruited and analyzed more than 170 MOWS-suspected cases. In 2014, we published an article summarizing 40 cases of Japanese MOWS cases, their phenotypes, types of ZEB2 mutation, et al [Yamada et al. Am J Med Genet A. 2014]. We continue to recruit and analyze MOWS cases.
Other our major researches are as follows.
１．We analyzed corticobasal degenerations of unknown etiology and identified three causative gene, SLC19A3, HIBCH, and ECHS1 [Yamada K et al. BMC Med Genet. 2010; Yamada K et al. Mol Genet Metab Rep. 2014; Yamada K et al. J Med Genet. 2015]. Now we are ready to analyze cases suspected to have a mutation of SLC19A3 or ECHS1.
２．We examined the diagnosis and therapy of PIK3CA-related overgrowth spectrum (PROS) harboring a mosaic PIK3CA mutation in the affected tissues. Metformin suppressed the activated PI3K/AKT/mTOR signaling pathway and the growth of fibroblasts of PROS, but did not show inhibition of the growth of control fibroblasts. These results show that metformin is a candidate drug for treating PROS in growing children [Suzuki et al. Oncotarget. 2017].
３．We examined a Japanese male patient with a de novo balanced reciprocal translocation t(12;20)(p12.1;p12.3) presenting a mild intellectual disability and dysmorphic features to identify a breakage of SOX5. We reported the patient as the first case of Lamb-Shaffer syndrome in Japan [Fukushi et al. Gene. 2018.].
４. We examined a Japanese male patient with a de novo pericentric inversion of chromosome 2 presenting mild intellectual disability and autistic behaviors. The analysis of the inversion breakpoints identified a new causative gene for intellectual disability, R3HDM1. This is the first report on R3HDM1 haploinsufficiency in the world [Fukushi et al. Am J Med Genet A. 2021].
５．We examined two female patients with different clinical features with almost same deletion at Xq27.3q28 and identified their severity was depending on status of X chromosome inactivation (XCI). Moreover, higher order chromatin structure (topologically associating domains, TADs) analysis using Hi-C database suggested that drastic TADs alteration and misexpression of genes in the neo-TAD. [Katoh et al. Hum Mutat. 2020].
Now we are recruiting the patients who may be the following disorders. Please feel free to contact us!
#. Mowat-Wilson syndrome [OMIM: #235730]
#. Thiamine metabolism dysfunction syndrome-2 [#607483]
Shin Hayashi, M.D., Ph.D. Chief of the department shin-hayashi@inst-hsc.jp
・軽度知的障害と自閉症様の行動を示し、de novoの2番染色体逆位を伴う症例の解析を行い、その研究成果を世界初のR3HDM1欠損症としてAm J Med Genet A誌に発表しました。(2021/5/22)
・Xq27.3q28領域に欠失を持つ女性症例2例の解析と病態形成機序の考察を行い、症例報告しました。(2020/7/27)
・尿酸代謝に影響を及ぼす遺伝性の代謝異常症の一つである、Lesch-Nyhan症候群に関する現在までの研究成果を、総説としてまとめました。(2020/7/1)
・軽度知的障害と自閉症が見られ、de novoの染色体相互転座を伴う症例の転座断点部位の解析を行い、その研究成果を本邦初のLamb-Shaffer症候群としてGene誌に発表しました。(2018/4/11)
・過成長症候群のひとつであるPIK3CA-related overgrowth spectrum (PROS)の診断方法の開発と治療方法の検討を行い、その研究成果をOncotarget誌に発表しました。(2017/7/27)
・SLC19A3欠損症の病態解明とチアミンによる治療の効果を検証し、その研究成果をPLoS One誌に発表しました。(2017/7/26)
・2番染色体（2p24.3-pter）重複と5番染色体（5p14.3-pter）欠失を伴い、重度知的障害が見られる姉弟例の染色体転座断点部位の解析を行い、その研究成果をAm J Med Genet A誌に発表しました。(2017/7/26)
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.
