The pathogenic mechanisms of severe intellectual disabiIity caused by PLEKHA5 or SLC19A3 mutations studied using mouse models of the diseases.

使用疾病小鼠模型研究了 PLEKHA5 或 SLC19A3 突变引起的严重智力障碍的致病机制。

• 批准号: 21390319
• 负责人: WAKAMATSU Nobuaki
• 金额: $ 11.23万
• 依托单位: Institute for Developmental Research, Aichi Human Service Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390319/
• 关键词: 小児神経学; 重度知的障害; 病因遺伝子; PLEKHA5; SLC19A3; 疾患モデルマウス; 重度精神遅滞; 遺伝子改変マウス; 精神遅滞; ノックインマウス; Sandhoff病

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.

我们确定了与两种不同疾病相关的候选基因突变，这些疾病的特征是严重的智力残疾。例1为平衡易位t(6；12)(q16；pl2)。我们分析了熊本大学用外显子陷阱方法培育的纯合子Plekha5基因敲除小鼠的大脑。小鼠存活1年以上，苏木精-伊红染色未见典型病理改变。提示该易位导致的PLEKHA5单倍体缺失和融合蛋白(由SFRS18启动子驱动的C端PLEKHA5表达)参与了患者1的发病机制。对由常规或Cre/loxP系统产生的Plekha5基因敲除小鼠进行分析，以确定Plekha5基因缺陷小鼠的表型。例2有严重的智能障碍和特殊的磁共振成像表现，包括基底节密度异常和严重的脑萎缩。我们在患者中发现了编码硫胺(维生素B1)转运蛋白的SLC19A3错义突变(E320Q)，并产生了一只与患者具有相同突变的敲入(NI)小鼠。当喂食标准小鼠饲料CE-2(Clea Japan Inc.，日本东京)时，NI小鼠存活超过1年。然而，当给纯合子NI小鼠提供含有35%维生素B1的特殊饲料CE-2时，它们在24天后死亡，但该饲料不影响野生型和杂合子NI小鼠的存活。提示SLC19A3基因E320Q突变患者对维生素B1具有特异性敏感性，服用大剂量维生素B1是可能的治疗方法。

项目成果

ダウン症候群小児における血清尿酸値の検討

唐氏综合症患儿血清尿酸水平的检查

• 发表时间: 2010
• 作者: 村松友佳子;西恵理子;谷合弘子;山田裕一;若松延昭;久保田優;水野誠司
• 通讯作者: 水野誠司

Mowat-Wilson症候群典型例におけるZFHXIB遺伝子変異

Mowat-Wilson综合征典型病例ZFHXIB基因突变

• 发表时间: 2010
• 作者: 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;黒澤健司;斎藤加代子;若松延昭
• 通讯作者: 若松延昭

Identification and characterization of splicing variants ofPLEKHA5 (Plekha5) during brain development.

大脑发育过程中 PLEKHA5 (Plekha5) 剪接变体的鉴定和表征。

• DOI: 10.1016/j.gene.2011.10.018
• 发表时间: 2012
• 期刊: Gene
• 影响因子: 3.5
• 作者: Yamada K;Nomura N;Yamano A;Yamada Y;Wakamatsu N
• 通讯作者: Wakamatsu N

Molecular analysis of two enzyme genes, HPRT1 and PRPS1, causing X-Hnked inborn errors of purine metabolism.

对导致嘌呤代谢 X-Hnked 先天性错误的两种酶基因 HPRT1 和 PRPS1 进行分子分析。

• DOI: 10.1080/15257771003738691
• 发表时间: 2010
• 期刊: Nucleosides Nucleotides Nucleic Acids
• 作者: Yamada Y;Yamada K;Nomura N;Yamano A;Kimura R;Tomida S;Naiki M;Wakamatsu N
• 通讯作者: Wakamatsu N

HPRT欠損症の原因となる新たなHPRT1遺伝子変異．

导致 HPRT 缺陷的新 HPRT1 基因突变。

• 发表时间: 2013
• 作者: Natsumi Kaneko;Andrea Vierkoetter;Ursula Kraemer;Dany Perner;Dorothee Sugiri;Mary Matsui;Ai Yamamoto;Jean Krutmann and Akimichi Morita;山田裕一
• 通讯作者: 山田裕一