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。

基本信息

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

项目摘要

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.

我们确定了与以严重智力残疾为特征的2种不同疾病相关的候选基因中的突变。患者1具有平衡的易位t（6; 12）（ql6; pL2）。我们分析了Kumamoto University使用外显子Trap方法产生的纯合PLEKHA5敲除小鼠的大脑。小鼠幸存了1年以上，苏木精 - 欧世毒素染色未指出典型的病理发现。结果表明，PLEKHA5和融合蛋白（由SFRS18启动子驱动的C-末端PLEKHA5表达）由易位引起的患者1涉及患者1的发病机理。系统对于确认plekha5缺乏小鼠的表型是必要的。患者2患有严重的智力障碍和特定的磁共振成像发现，包括基底神经节的异常密度和严重的脑萎缩。我们在SLC19A3中鉴定了一个编码硫胺素（维生素B1）转运蛋白的错义突变（E320Q），并产生了一种与患者相同的敲入（Ni）小鼠。当Fed Standard Mouse Chow（CE-2）（Clea Japan Inc.，Tokyo，Japan，Japan）中，NI小鼠幸存了1年以上。但是，当提供含有35％维生素B1的特殊饲料CE-2时，它们在24天后死亡；但是，饲料不影响野生型和杂合Ni小鼠的存活。这些结果表明，在SLC19A3中携带E320Q突变的患者对维生素B1具有特异性的敏感性，而高剂量维生素B1的摄入可能是患者的治疗方法。