Abstract
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.
Highlights
The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members
Because nutrients derived from the mother’s plasma and delivered to the fetus have to be transported through the vascular endothelium of the placenta and brain, we hypothesized that SLC27A3 and SLC27A4, both of which are expressed in placenta and brain endothelial cells, are the most relevant fatty acid transporters for supplying fatty acids to the fetal brain (Fig. 1)[12,13,14,15]
We focused on two FATP proteins, FATP3 and FATP4, because these proteins may be key molecules for fatty acid uptake into the fetal brain (Fig. 1)
Summary
The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. We showed that a SLC27A4 Ser[209] mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd[3] cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly[209], suggesting that the functional change may contribute to ASD pathophysiology. Because nutrients derived from the mother’s plasma and delivered to the fetus have to be transported through the vascular endothelium of the placenta and brain, we hypothesized that SLC27A3 and SLC27A4, both of which are expressed in placenta and brain endothelial cells, are the most relevant fatty acid transporters for supplying fatty acids to the fetal brain (Fig. 1)[12,13,14,15]
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