title: Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.
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.
authors.affiliation: Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria.
authors.forename: Dora C
authors.initials: DC
authors.lastname: Tărlungeanu
authors.affiliation: Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria.
authors.forename: Elena
authors.initials: E
authors.lastname: Deliu
authors.affiliation: Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria.
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Dotter
authors.affiliation: Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
authors.forename: Majdi
authors.initials: M
authors.lastname: Kara
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20251, Germany.
authors.forename: Philipp Christoph
authors.initials: PC
authors.lastname: Janiesch
authors.affiliation: Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Mariafrancesca
authors.initials: M
authors.lastname: Scalise
authors.affiliation: Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Galluccio
authors.affiliation: Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria.
authors.forename: Mateja
authors.initials: M
authors.lastname: Tesulov
authors.affiliation: Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Morelli
authors.affiliation: Association of Developmental Child Neurology, Ankara, Turkey.
authors.forename: Fatma Mujgan
authors.initials: FM
authors.lastname: Sonmez
authors.affiliation: 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.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka Prefecture 565-0871, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ohgaki
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka Prefecture 565-0871, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Neuroscience, UCSD, Investigator, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, San Diego, CA 92093, USA.
authors.forename: Anide
authors.initials: A
authors.lastname: Johansen
authors.affiliation: Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
authors.forename: Seham
authors.initials: S
authors.lastname: Esharif
authors.affiliation: Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.affiliation: Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.
authors.forename: Meral
authors.initials: M
authors.lastname: Topcu
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Avner
authors.initials: A
authors.lastname: Schlessinger
authors.affiliation: Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Indiveri
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20251, Germany.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Duncan
authors.affiliation: 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.
authors.forename: Ahmet Okay
authors.initials: AO
authors.lastname: Caglayan
authors.affiliation: 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.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Department of Neuroscience, UCSD, Investigator, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, San Diego, CA 92093, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.affiliation: Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria. Electronic address: gnovarino@ist.ac.at.
authors.forename: Gaia
authors.initials: G
authors.lastname: Novarino
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010375:Pedigree; D014176:Protein Biosynthesis; D042787:Receptor, TIE-2 / Q000235:genetics
chemical_list: D000596:Amino Acids; D027283:Large Neutral Amino Acid-Transporter 1; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
keywords: ASD; amino acid transporter; autism; blood brain barrier; excitation and inhibition imbalance; motor deficits