Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder

Tarlungeanu, Dora and Deliu, Elena and Dotter, Christoph P and Kara, Majdi and Janiesch, Philipp C and Scalise, Mariafrancesca and Galluccio, Michele and Tesulov, Mateja and Morelli, Emanuela and Sönmez, Fatma M and Bilgüvar, Kaya and Ohgaki, Ryuichi and Kanai, Yoshikatsu and Johansen, Anide and Esharif, Seham and Ben-Omran, Tawfeg I and Topcu, Meral F and Schlessinger, Avner and Indiveri, Cesare and Duncan, Kent E and Caglayan, Ahmet O and Günel, Murat and Gleeson, Joseph G and Novarino, Gaia (2016) Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell, 167 (6). pp. 1481-1494. ISSN 0092-8674

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Official URL: http://dx.doi.org/10.1016/j.cell.2016.11.013

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.

Item Type: Article
DOI: 10.1016/j.cell.2016.11.013
Uncontrolled Keywords: Autism, amino acid transporter, ASD, blood brain barrier, excitation and inhibition imbalance, motor deficits
Subjects: 500 Science > 570 Life sciences; biology > 576 Genetics and evolution
600 Technology > 610 Medicine and health > 616 Diseases
Research Group: Novarino Group
SWORD Depositor: Sword Import User
Depositing User: Sword Import User
Date Deposited: 24 Feb 2017 08:04
Last Modified: 21 Dec 2017 12:12
URI: https://repository.ist.ac.at/id/eprint/771

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