Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to decreased levels of brain BCAAs, abnormal mRNA translation and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function. RNA-sequencing of cerebellum from 3 wildtype mice and 3 Slc7a5 KO mice孤独症谱系障碍（Autism spectrum disorders, ASD）是一类常与其他神经系统疾病存在重叠的遗传性疾病。我们此前曾报道支链氨基酸（branched chain amino acid, BCAA）分解代谢通路异常可导致ASD。本研究证实，定位于血脑屏障（blood brain barrier, BBB）的大型中性氨基酸转运蛋白溶质载体转运蛋白7a5（solute carrier transporter 7a5, SLC7A5）在维持大脑正常BCAA水平中发挥不可或缺的作用。在小鼠模型中，敲除血脑屏障内皮细胞中的Slc7a5基因会导致大脑BCAA水平降低、信使RNA（mRNA）翻译异常以及严重的神经系统异常。此外，我们还鉴定出数名携带SLC7A5基因有害纯合突变的患者，其表现出自闭症特征与运动发育迟缓。最终，我们证实通过脑室内给予BCAA可改善成年突变小鼠的异常行为。本研究阐明了由SLC7A5突变所定义的神经系统综合征，并支持BCAA在人类大脑功能中发挥不可或缺的作用。本数据集包含3只野生型小鼠与3只Slc7a5基因敲除小鼠的小脑RNA测序（RNA-sequencing）数据。