Traduction: G.M.
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
Tărlungeanu DC1, Deliu E1, Dotter CP1, Kara M2, Janiesch PC3, Scalise M4, Galluccio M4, Tesulov M1, Morelli E1, Sonmez FM5, Bilguvar K6, Ohgaki R7, Kanai Y7, Johansen A8, Esharif S2, Ben-Omran T9, Topcu M10, Schlessinger A11, Indiveri C4, Duncan KE3, Caglayan AO12, Gunel M13, Gleeson JG8, Novarino G14.
Author information
- 1Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria.
- 2Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
- 3Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20251, Germany.
- 4Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Arcavacata di Rende, Italy.
- 5Association of Developmental Child Neurology, Ankara, Turkey.
- 6Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Yale Center for Genome Analysis, Yale School of Medicine, Orange, CT 06477, USA.
- 7Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka Prefecture 565-0871, Japan.
- 8Department of Neuroscience, UCSD, Investigator, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, San Diego, CA 92093, USA.
- 9Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
- 10Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.
- 11Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
- 12Department 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.
- 13Departments 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.
- 14Institute of Science and Technology (IST) Austria, Klosterneuburg 3400, Austria. Electronic address: gnovarino@ist.ac.at
Abstract
Les
troubles du spectre de l'autisme (TSA) sont un groupe de troubles
génétiques se chevauchant souvent avec d'autres conditions neurologiques. Nous
avons décrit précédemment des anomalies dans la voie catabolique des
acides aminés à chaîne ramifiée (BCAA) comme cause de TSA. Ici,
nous montrons que le transporteur porteur de soluté 7a5 (SLC7A5), un
grand transporteur d'acides aminés neutres localisé à la barrière
hémato-encéphalique (BBB), a un rôle essentiel dans le maintien des
niveaux normaux de BCAAs du cerveau. Chez
la souris, la délétion de Slc7a5 des cellules endothéliales de la BHE
conduit à un profil atypique des acides aminés du cerveau, à une
traduction anormale de l'ARNm et à des anomalies neurologiques graves. De
plus, nous avons identifié plusieurs patients avec des traits
autistiques et un retard moteur portant des mutations homozygotes
délétères dans le gène SLC7A5. Enfin,
nous démontrons que l'administration intracérébroventriculaire de BCAA
améliore les comportements anormaux chez les souris mutantes adultes. Nos données élucident un syndrome neurologique défini par les mutations
SLC7A5 et supportent l'idée d'un rôle essentiel du BCAA dans la fonction
cérébrale humaine.
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.
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
- PMID: 27912058
- DOI: 10.1016/j.cell.2016.11.013
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