Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Brain. 2010 May;133(Pt 5):1391-402. doi: 10.1093/brain/awq071. Epub 2010 Apr 15.
We have studied a family with severe mental retardation characterized by the virtual absence of speech, autism spectrum disorder, epilepsy, late-onset ataxia, weakness and dystonia. Post-mortem examination of two males revealed widespread neuronal loss, with the most striking finding being neuronal and glial tau deposition in a pattern reminiscent of corticobasal degeneration. Electron microscopic examination of isolated tau filaments demonstrated paired helical filaments and ribbon-like structures. Biochemical studies of tau demonstrated a preponderance of 4R tau isoforms. The phenotype was linked to Xq26.3, and further analysis identified an in-frame 9 base pair deletion in the solute carrier family 9, isoform A6 (SLC9A6 gene), which encodes sodium/hydrogen exchanger-6 localized to endosomal vesicles. Sodium/hydrogen exchanger-6 is thought to participate in the targeting of intracellular vesicles and may be involved in recycling synaptic vesicles. The striking tau deposition in our subjects reveals a probable interaction between sodium/proton exchangers and cytoskeletal elements involved in vesicular transport, and raises the possibility that abnormalities of vesicular targeting may play an important role in more common disorders such as Alzheimer's disease and autism spectrum disorders.
我们研究了一个有严重精神发育迟滞的家系，其特征为几乎完全丧失语言能力、自闭症谱系障碍、癫痫、发病较晚的共济失调、虚弱和肌张力障碍。对两名男性进行的尸检显示广泛的神经元丧失，最显著的发现是神经元和神经胶质纤维缠结在类似于皮质基底节变性的模式中沉积。对分离的 tau 丝的电子显微镜检查显示出双螺旋丝和带状结构。tau 的生化研究表明 4R tau 同工型占优势。表型与 Xq26.3 相关，进一步分析确定溶质载体家族 9，同工型 A6（SLC9A6 基因）中有一个 9 个碱基对的无框缺失，该基因编码位于内体小泡中的钠/氢交换器-6。钠/氢交换器-6 被认为参与细胞内小泡的靶向，并且可能参与突触小泡的再循环。我们研究对象中的 tau 沉积明显表明钠离子/质子交换器与参与囊泡运输的细胞骨架元件之间可能存在相互作用，并提出囊泡靶向异常可能在更常见的疾病（如阿尔茨海默病和自闭症谱系障碍）中发挥重要作用。
