--- _id: '1183' abstract: - lang: eng text: 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. acknowledgement: "This work was supported by NICHD (P01HD070494) and SFARI (grant 275275) to J.G.G., and FWF (SFB35_3523) to G.N.\r\nWe thank A.C. Manzano, Mike Liu, and F. Marr for technical assistance, and R. Shigemoto and the IST Austria Electron Microscopy (EM) Facility for assistance. We acknowledge support from CIDR for genome-wide SNP analysis (X01HG008823) and Broad Institute Center for Mendelian Disorders (UM1HG008900 to D. MacArthur), the Yale Center for Mendelian Disorders (U54HG006504 to M.G.), the Gregory M. Kiez and Mehmet Kutman Foundation (M.G.), Italian Ministry of Instruction University and Research (PON01_00937 to C.I.), and NIH (R01-GM108911 to A.S.). This work was supported by NICHD (P01HD070494) and SFARI (grant 275275) to J.G.G., and FWF (SFB35_3523) to G.N.\r\n\r\n#EMFacility" article_processing_charge: No article_type: original author: - first_name: Dora-Clara full_name: Tarlungeanu, Dora-Clara id: 2ABCE612-F248-11E8-B48F-1D18A9856A87 last_name: Tarlungeanu - first_name: Elena full_name: Deliu, Elena id: 37A40D7E-F248-11E8-B48F-1D18A9856A87 last_name: Deliu orcid: 0000-0002-7370-5293 - first_name: Christoph full_name: Dotter, Christoph id: 4C66542E-F248-11E8-B48F-1D18A9856A87 last_name: Dotter orcid: 0000-0002-9033-9096 - first_name: Majdi full_name: Kara, Majdi last_name: Kara - first_name: Philipp full_name: Janiesch, Philipp last_name: Janiesch - first_name: Mariafrancesca full_name: Scalise, Mariafrancesca last_name: Scalise - first_name: Michele full_name: Galluccio, Michele last_name: Galluccio - first_name: Mateja full_name: Tesulov, Mateja last_name: Tesulov - first_name: Emanuela full_name: Morelli, Emanuela id: 3F4D1282-F248-11E8-B48F-1D18A9856A87 last_name: Morelli - first_name: Fatma full_name: Sönmez, Fatma last_name: Sönmez - first_name: Kaya full_name: Bilgüvar, Kaya last_name: Bilgüvar - first_name: Ryuichi full_name: Ohgaki, Ryuichi last_name: Ohgaki - first_name: Yoshikatsu full_name: Kanai, Yoshikatsu last_name: Kanai - first_name: Anide full_name: Johansen, Anide last_name: Johansen - first_name: Seham full_name: Esharif, Seham last_name: Esharif - first_name: Tawfeg full_name: Ben Omran, Tawfeg last_name: Ben Omran - first_name: Meral full_name: Topcu, Meral last_name: Topcu - first_name: Avner full_name: Schlessinger, Avner last_name: Schlessinger - first_name: Cesare full_name: Indiveri, Cesare last_name: Indiveri - first_name: Kent full_name: Duncan, Kent last_name: Duncan - first_name: Ahmet full_name: Caglayan, Ahmet last_name: Caglayan - first_name: Murat full_name: Günel, Murat last_name: Günel - first_name: Joseph full_name: Gleeson, Joseph last_name: Gleeson - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Tarlungeanu D-C, Deliu E, Dotter C, et al. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell. 2016;167(6):1481-1494. doi:10.1016/j.cell.2016.11.013 apa: Tarlungeanu, D.-C., Deliu, E., Dotter, C., Kara, M., Janiesch, P., Scalise, M., … Novarino, G. (2016). Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell. Cell Press. https://doi.org/10.1016/j.cell.2016.11.013 chicago: Tarlungeanu, Dora-Clara, Elena Deliu, Christoph Dotter, Majdi Kara, Philipp Janiesch, Mariafrancesca Scalise, Michele Galluccio, et al. “Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.” Cell. Cell Press, 2016. https://doi.org/10.1016/j.cell.2016.11.013. ieee: D.-C. Tarlungeanu et al., “Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder,” Cell, vol. 167, no. 6. Cell Press, pp. 1481–1494, 2016. ista: Tarlungeanu D-C, Deliu E, Dotter C, Kara M, Janiesch P, Scalise M, Galluccio M, Tesulov M, Morelli E, Sönmez F, Bilgüvar K, Ohgaki R, Kanai Y, Johansen A, Esharif S, Ben Omran T, Topcu M, Schlessinger A, Indiveri C, Duncan K, Caglayan A, Günel M, Gleeson J, Novarino G. 2016. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell. 167(6), 1481–1494. mla: Tarlungeanu, Dora-Clara, et al. “Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.” Cell, vol. 167, no. 6, Cell Press, 2016, pp. 1481–94, doi:10.1016/j.cell.2016.11.013. short: D.-C. Tarlungeanu, E. Deliu, C. Dotter, M. Kara, P. Janiesch, M. Scalise, M. Galluccio, M. Tesulov, E. Morelli, F. Sönmez, K. Bilgüvar, R. Ohgaki, Y. Kanai, A. Johansen, S. Esharif, T. Ben Omran, M. Topcu, A. Schlessinger, C. Indiveri, K. Duncan, A. Caglayan, M. Günel, J. Gleeson, G. Novarino, Cell 167 (2016) 1481–1494. date_created: 2018-12-11T11:50:35Z date_published: 2016-12-01T00:00:00Z date_updated: 2024-03-27T23:30:12Z day: '01' ddc: - '576' - '616' department: - _id: GaNo doi: 10.1016/j.cell.2016.11.013 file: - access_level: open_access checksum: 7fe01ab12a6610d3db421e0136db2f77 content_type: application/pdf creator: system date_created: 2018-12-12T10:13:44Z date_updated: 2020-07-14T12:44:37Z file_id: '5030' file_name: IST-2017-771-v1+1_Tarlungeanu_et_al._Final_edited.pdf file_size: 73907957 relation: main_file file_date_updated: 2020-07-14T12:44:37Z has_accepted_license: '1' intvolume: ' 167' issue: '6' language: - iso: eng month: '12' oa: 1 oa_version: Submitted Version page: 1481 - 1494 project: - _id: 25473368-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: F03523 name: Transmembrane Transporters in Health and Disease publication: Cell publication_status: published publisher: Cell Press publist_id: '6170' pubrep_id: '771' quality_controlled: '1' related_material: record: - id: '395' relation: dissertation_contains status: public scopus_import: '1' status: public title: Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder type: journal_article user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 volume: 167 year: '2016' ...