Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.
Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.
复制标题
DOI：
10.1038/srep16239
复制
发表时间：
2015-11-09
影响因子：
4.6
通讯作者：
Yoshikawa T
中科院分区：
文献类型：
--
作者：
Maekawa M;Iwayama Y;Ohnishi T;Toyoshima M;Shimamoto C;Hisano Y;Toyota T;Balan S;Matsuzaki H;Iwata Y;Takagai S;Yamada K;Ota M;Fukuchi S;Okada Y;Akamatsu W;Tsujii M;Kojima N;Owada Y;Okano H;Mori N;Yoshikawa T
溶质载体27A（SLC27A）基因家族编码脂肪酸转运蛋白（FATPs），包括6个成员。在胎儿和出生后的发育阶段，大脑的发育需要可靠的脂肪酸供应。由于自闭症谱系障碍（ASD）现在被认为是由早期大脑发育受损引起的疾病，因此SLC27A基因的功能异常可能有助于ASD的发病机制。在此，我们证实了SLC27A3和SLC27A4在来源于人诱导多能干细胞的人神经干细胞中的表达，这表明它们参与中枢神经系统的发育阶段。此外，我们使用267名ASD患者和1140名对照样本对SLC27A3和SLC27A4基因进行了重新测序，并分别检测到SLC27A3和SLC27A4的47种（44种新的和29种非同义的）和30种（17种新的和14种非同义的）变体，揭示了它们具有高度多态性，具有多种罕见变体。SLC27A4 Ser209等位基因在ASD样本中更常见。此外，我们发现，SLC27A4 Ser209突变体导致bEnd3细胞（一种小鼠脑毛细血管来源的内皮细胞系）的荧光标记脂肪酸摄取显著高于SLC27A4 Gly209，这表明功能变化可能有助于ASD病理生理学。
The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.