2012 Fiscal Year Final Research Report
The pathogenic mechanisms of severe intellectual disabiIity caused by PLEKHA5 or SLC19A3 mutations studied using mouse models of the diseases.
| Project/Area Number |
21390319
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Institute for Developmental Research, Aichi Human Service Center |
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Principal Investigator |
WAKAMATSU Nobuaki 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 部長 (60274198)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Yasukazu 愛知県心身障害者コロニー発達障害研究所, 遺伝子学部, 室長 (70191343)
YAMADA Kenichiro 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 主任研究員 (30291173)
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| Co-Investigator(Renkei-kenkyūsha) |
MIZUNO Seiji 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 研究員 (20393150)
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| Project Period (FY) |
2009 – 2012
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| Keywords | 小児神経学 |
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| Research Abstract |
We identified mutations in candidate genes associated with 2 different diseases characterized by severe intellectual disability. Patient 1 had a balanced translocation t(6;12)(ql6;pl2). We analyzed the brains of homozygous Plekha5 knockout mice produced using exon trap method at the Kumamoto University. The mice survived more than 1 year, and typical pathological findings were not noted by hematoxylin-eosin staining. The results suggested that haploinsufficiency of PLEKHA5 and a fusion protein (c-terminal PLEKHA5 expression driven by SFRS18 promoter) caused by the translocation were involved in the pathogenesis of the disease in patient 1. Analysis of Plekha5 knockout mice produced by conventional or Cre/loxP system is necessary to confirm the phenotype of Plekha5 deficient mouse. Patient 2 had severe intellectual disability and specific magnetic resonance imaging findings, including abnormal density of basal ganglions and severe brain atrophy. We identified a missense mutation (E320Q) in SLC19A3 encoding thiamine (vitamin B1) transporter in the patient and generated a knock-in (NI) mouse that had the equivalent mutation as in the patient. The NI mice survived more than 1 year when fed standard mouse chow, CE-2 (Clea Japan Inc., Tokyo, Japan). However, when the homozygous NI mice were provided special feed CE-2 containing 35% vitamin B1, they died after 24 days; however, the feed did not affect the survival of wild-type and heterozygous NI mice. Theses results suggest that the patients harboring E320Q mutation in SLC19A3 have specific sensitivity for vitamin B1, and intake of high dose vitamin B1 is the possible treatment for the patients.
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[Journal Article] Genotype-phenotype correlations in neurogenetics : Lesch-Nyhan disease as a model disorder.2013
Author(s)
Fu R, Ceballos-Picot I, Torres R, Larovere L, Yamada Y, Nguyen KV, Hegde M, Visser JE, Schretlen DJ, Nyhan WL, Puig JQ O'Neill PJ, Jinnah HA, for the Lesch-Nyhan Disease International Study Group
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Journal Title
Peer Reviewed
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[Journal Article] Molecular analysis of X-lmked inborn errors of purine metabolism : HPRT1 and PRPS1 mutations.2011
Author(s)
Yamada Y, Yamada K, Nomura N, Yamano A, Kimura R, Naiki M, Fukushi D, Wakamatsu N, Taniguchi A, Kaneko K, Fujimori S
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Journal Title
Nucleosides Nucleotides Nucleic Acids
Volume: 30
Pages: 1272-1275
DOI
Peer Reviewed
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[Journal Article] A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations.2010
Author(s)
Yamada K, Miura K, Hara K, Suzuki M, Nakanishi K, Kumagai T, Ishihara N, Yamada Y, Kuwano R, Tsuji S, Wakamatsu N
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Journal Title
BMC Medical Genetics
Volume: 11
Pages: 171
DOI
Peer Reviewed
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[Presentation] 末梢神経障害と副甲状腺機能低下症を伴ったミトコンドリア三頭酵素(MTP)欠損症.2013
Author(s)
内木美紗子, 越知信彦, 加藤有介, Jamiyan Purevsuren, 山田憲一郎, 原 紳也, 木村礼子, 山田裕一, 熊谷俊幸, 山口清次, 若松延昭
Organizer
東海臨床遺伝・代謝懇話会
Place of Presentation
名古屋
Year and Date
2013-02-12
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[Presentation] BRESEK/BRESHECK syndrome and IFAP syndrome are allelic disorder caused by mutation in MBTPS2.2012
Author(s)
Mizuno S, Naiki M, Yamada K, Yamada Y, Kimura R, Oshiro M, Okamoto N, Makita Y, Seishima M, Wakamatsu N
Organizer
European Human Genetics Conference 2012
Place of Presentation
Niirnberg, Germany
Year and Date
2012-06-24
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[Presentation] Mowat-Wilson症候群におけるZEB2遺伝子解析2011
Author(s)
山田裕一, 山田憲一郎, 水野誠司, 西恵理子, 石原尚子, 今高城治, 鈴木由香, 鮫島希代子, 秋丸憲子, 松田圭子, 岡本伸彦, 平木洋子, 若松延昭
Organizer
日本人類遺伝学会/東アジア人類遺伝学会共同大会
Place of Presentation
千葉
Year and Date
2011-11-10
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[Presentation] A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations.2011
Author(s)
Yamada K, Miura K, Hara K, Suzuki M, Nakanishi K, Kumagai T, Ishihara N, Yamada Y, Kuwano R, Tsuji S, Wakamatsu N
Organizer
International Congress of Human Genetics and Annual Meeting of the American Society of Human Genetics
Place of Presentation
Montreal, Canada
Year and Date
2011-10-13
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[Presentation] Molecular analysis of ZEB2 responsible for the Mowat-Wilson syndrome.2011
Author(s)
Yamada Y, Yamada K, Mizuno S, Nishi E, Ishihara N, Akimaru N, Urano M, Matsuda K, Okamoto N, Hiraki Y4, Wakamatsu N
Organizer
International Congress of Human Genetics and Annual Meeting of the American Society of Human Genetics
Place of Presentation
Montreal, Canada
Year and Date
2011-10-13
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[Presentation] 多様な臨床症状と脳MRI画像を呈するSLC19A3異常症2011
Author(s)
山田憲一郎, 三浦清邦, 原 賢寿, 鈴木基正, 中西圭子, 熊谷俊幸, 石原尚子, 山田裕一, 桑野良三, 辻 省次, 若松延昭
Organizer
東海臨床遺伝・代謝懇話会
Place of Presentation
名古屋
Year and Date
2011-02-01
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[Presentation] Mowat-Wilson症候群典型例にみられた新しいZFHXIB遺伝子変異2010
Author(s)
山田裕一, 山田憲一郎, 水野誠司, 古谷憲孝, 松尾真理, 浦野真理, 平木洋子, 秋丸憲子, 松田圭子, 岡本伸彦, 黒澤健司, 斎藤加代子, 若松延昭
Organizer
日本生化学会日本分子生物学会合同大会
Place of Presentation
東京
Year and Date
2010-12-10
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[Presentation] Novel mutations of ZFHX1B responsible for the typical cases of Mowat-Wilson syndrome.2010
Author(s)
YamadaY, Yamada K, Mizuno S, Furuya N, Matsuo M, Urano M, Hiraki Y, Kurosawa K, Saito K, Wakamatsu N
Organizer
Annual Meeting of the American Society of Human Genetics
Place of Presentation
Washington DC, USA
Year and Date
2010-11-05
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[Book] Aneuploidy and intellectual disability, in Aneuploidy in Health and Disease, Storchova Z ed, InTech-Open Access Publisher2012
Author(s)
Fukushi D, Mizuno S, Yamada K, Kimura R, Yamada Y, Kumagai T, Wakamatsu N
Total Pages
107-122
Publisher
Rijeka, Croatia
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