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

• Published in: Cell Vol. 167; no. 6; pp. 1481 - 1494.e18
• Main Authors: Tărlungeanu, Dora C., Deliu, Elena, Dotter, Christoph P., Kara, Majdi, Janiesch, Philipp Christoph, Scalise, Mariafrancesca, Galluccio, Michele, Tesulov, Mateja, Morelli, Emanuela, Sonmez, Fatma Mujgan, Bilguvar, Kaya, Ohgaki, Ryuichi, Kanai, Yoshikatsu, Johansen, Anide, Esharif, Seham, Ben-Omran, Tawfeg, Topcu, Meral, Schlessinger, Avner, Indiveri, Cesare, Duncan, Kent E., Caglayan, Ahmet Okay, Gunel, Murat, Gleeson, Joseph G., Novarino, Gaia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016
• Subjects: abnormal behavior; adults; amino acid composition; amino acid transporter; amino acids; Amino Acids - administration & dosage; Amino Acids - metabolism; Animals; ASD; autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - pathology; Autism Spectrum Disorder - physiopathology; blood brain barrier; Blood-Brain Barrier - physiopathology; brain; Brain - metabolism; Brain - pathology; Brain - physiopathology; endothelial cells; excitation and inhibition imbalance; Female; genes; genetic disorders; homozygosity; Humans; Infant; Infant, Newborn; Large Neutral Amino Acid-Transporter 1 - genetics; Large Neutral Amino Acid-Transporter 1 - metabolism; Male; messenger RNA; Mice; Mice, Knockout; motor deficits; mutants; Mutation; patients; Pedigree; Protein Biosynthesis; Receptor, TIE-2 - genetics; solutes; translation (genetics); blood brain barrier; excitation and inhibition imbalance; ASD; motor deficits; autism; amino acid transporter
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2016.11.013

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. [Display omitted] •Slc7a5 is critical for maintaining normal brain BCAA levels•Brain BCAA deficiency triggers neurobehavioral alterations in mice•Patients with SLC7A5 mutations have ASD and motor delay•Slc7a5 mutant mouse behavior is partially corrected by BCAA injections Mutations in a solute carrier protein that blunts the transport of branched-chain amino acids lead to neurological and behavioral abnormalities associated with autism spectrum disorder.