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

TitleImpaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.
Publication TypeJournal Article
Year of Publication2016
AuthorsTărlungeanu, DC, Deliu, E, Dotter, CP, Kara, M, Janiesch, PChristoph, Scalise, M, Galluccio, M, Tesulov, M, Morelli, E, Sonmez, FMujgan, Bilguvar, K, Ohgaki, R, Kanai, Y, Johansen, A, Esharif, S, Ben-Omran, T, Topcu, M, Schlessinger, A, Indiveri, C, Duncan, KE, Çağlayan, AOkay, Günel, M, Gleeson, JG, Novarino, G
Date Published2016 Dec 01
KeywordsAmino Acids, Animals, Autism Spectrum Disorder, Blood-Brain Barrier, Brain, Female, Humans, Infant, Infant, Newborn, Large Neutral Amino Acid-Transporter 1, Male, Mice, Mice, Knockout, Mutation, Pedigree, Protein Biosynthesis, Receptor, TIE-2

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.

Alternate JournalCell
PubMed ID27912058
PubMed Central IDPMC5554935
Grant ListP01 HD070494 / HD / NICHD NIH HHS / United States
R01 GM108911 / GM / NIGMS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States