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

我们确定了与2种不同的以严重智力残疾为特征的疾病相关的候选基因突变。患者1具有平衡易位t（6;12）（ql 6; pl 2）。我们分析了熊本大学使用外显子捕获方法产生的纯合Plekha 5基因敲除小鼠的大脑。小鼠存活超过1年，苏木精-伊红染色未观察到典型的病理学发现。结果表明，PLEKHA 5的单倍不足和融合蛋白（由SFRS 18启动子驱动的C-末端PLEKHA 5表达）的易位所导致的疾病的发病机制参与患者1。对常规或Cre/loxP系统产生的Plekha 5基因敲除小鼠进行分析是确认Plekha 5基因敲除小鼠表型的必要条件。患者2有严重的智力残疾和特定的磁共振成像结果，包括基底节密度异常和严重的脑萎缩。我们在患者中确定了编码硫胺素（维生素B1）转运蛋白的SLC 19 A3中的错义突变（E320 Q），并产生了具有与患者相同突变的敲入（NI）小鼠。当喂食标准小鼠食物CE-2（Clea Japan Inc.，日本东京）。然而，当纯合子NI小鼠被提供含有35%维生素B1的特殊饲料CE-2时，它们在24天后死亡;然而，饲料不影响野生型和杂合子NI小鼠的存活。提示SLC 19 A3基因E320 Q突变的患者对维生素B1具有特异性敏感性，大剂量维生素B1摄入是治疗的可能途径。

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.