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Cell. 2016 Dec 1;167(6):1481-1494.e18. doi: 10.1016/j.cell.2016.11.013.

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

Author information

1
Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria.
2
Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
3
Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20251, Germany.
4
Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Arcavacata di Rende, Italy.
5
Association of Developmental Child Neurology, Ankara, Turkey.
6
Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Yale Center for Genome Analysis, Yale School of Medicine, Orange, CT 06477, USA.
7
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka Prefecture 565-0871, Japan.
8
Department of Neuroscience, UCSD, Investigator, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, San Diego, CA 92093, USA.
9
Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
10
Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.
11
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12
Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul, Turkey; Departments of Neurosurgery, Genetics, and Neurobiology, Program in Brain Tumor Research, Yale Program on Neurogenetics and Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA.
13
Departments of Neurosurgery, Genetics, and Neurobiology, Program in Brain Tumor Research, Yale Program on Neurogenetics and Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA.
14
Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria. Electronic address: gnovarino@ist.ac.at.

Abstract

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 atypical brain amino acid profile, 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.

KEYWORDS:

ASD; amino acid transporter; autism; blood brain barrier; excitation and inhibition imbalance; motor deficits

PMID:
27912058
PMCID:
PMC5554935
DOI:
10.1016/j.cell.2016.11.013
[Indexed for MEDLINE]
Free PMC Article

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