Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder
Open accessAbstract
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.
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Deletion of Slc7a5 from the blood-brain barrier in mice does not lead to a reduction in brain size.
“while patients with SLC7A5 mutations present with microcephaly, the deletion of Slc7a5 from the BBB in mice (Slc7a5 fl/fl ;Tie2-Cre positive [+] mice) does not lead to a reduction in brain size.6”
From Large neutral amino acid levels tune perinatal neuronal excitability and survival (2023) · cites this paper as [6]
The Results describe the Tie2Cre;Slc7a5fl/fl BBB-deletion mice and report that their overall brain morphology was indistinguishable from controls (Figure S4A). The paper also says the mice appeared normal in size, but that refers to the animals; our copy does not directly report a brain-size measurement or explicitly rule out a reduction in brain size. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe constant features associated with biallelic pathogenic SLC7A5 variants include microcephaly, developmental and motor delay, seizures, and autistic features.
“The phenotypic comparison of published patients 6 revealed that the constant features associated with biallelic pathogenic SLC7A5 variants include microcephaly, developmental and motor delay, seizures, and autistic features (Table S1).”
From Large neutral amino acid levels tune perinatal neuronal excitability and survival (2023) · cites this paper as [6]
The Results section, “SLC7A5 mutations in patients with ASD and motor delay,” reports affected children with homozygous SLC7A5 variants, autistic features, microcephaly, and motor problems. It does not establish developmental delay or seizures as constant features of those patients; the Discussion mentions seizures in connection with a different disorder. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMutations in SLC7A5, a transporter of metabolically essential large neutral amino acids, are a rare cause of autism spectrum disorders.
“We recently identified mutations in the gene SLC7A5, encoding a large neutral amino acid (LNAA) transporter (LAT1), as a rare cause of autism spectrum disorders.6”
From Large neutral amino acid levels tune perinatal neuronal excitability and survival (2023) · cites this paper as [6]
Trio-WES analysis of both siblings and their parents identified compound heterozygous pathogenic variants in the SLC7A5 gene: the previously described and functionally assessed missense variant c.1124C>T, p.(Pro375Leu) and a novel intragenic deletion of exons 5 to 10.
“Trio-WES analysis of both siblings and their parents identified compound heterozygous pathogenic variants in the SLC7A5 gene: the previously described and functionally assessed missense variant c.1124C>T, p.(Pro375Leu) 6 and a novel intragenic deletion of exons 5 to 10.”
From Large neutral amino acid levels tune perinatal neuronal excitability and survival (2023) · cites this paper as [6]
The pathological variants identified in patients are mostly missense mutations that impact the transport capacity, not the expression, of the transporter.
“Notably, the pathological variants identified in patients are mostly missense mutations that impact the transport capacity, not the expression, of the transporter.6”
From Large neutral amino acid levels tune perinatal neuronal excitability and survival (2023) · cites this paper as [6]
Trio-whole exome sequencing identified compound heterozygous pathogenic variants in SLC7A5 in both siblings: the previously described missense variant c.1124C>T, p.(Pro375Leu) and a novel intragenic deletion of exons 5 to 10.
“Trio-whole exome sequencing (WES) analysis of both siblings and their parents identified compound heterozygous pathogenic variants in the SLC7A5 gene: the previously described and functionally assessed missense variant c.1124C>T, p.(Pro375Leu) 6 and a novel intragenic deletion of exons 5 to 10.”
From Large neutral amino acid levels tune perinatal neuronal excitability and survival (2023) · cites this paper as [6]
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- Authors
- Tărlungeanu, D. C., Deliu, E., Dotter, C. P., Kara, M., Janiesch, P. C., Scalise, M., Galluccio, M., Tesulov, M., Morelli, E., Sonmez, F. M., Bilguvar, K., Ohgaki, R., Kanai, Y., Johansen, A., Esharif, S., Ben-Omran, T., Topcu, M., Schlessinger, A., Indiveri, C., Duncan, K. E., Caglayan, A. O., Gunel, M., Gleeson, J. G., & Novarino, G.
- Affiliations
- Institute of Science and Technology Austria (AT)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Calabria (IT)
- The University of Osaka (JP)
- Howard Hughes Medical Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Novarino, Gaia
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 167
- Issue
- 6
- Pages
- 1481-1494.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5554935
- OpenAlex
- W2557876966
- Cited by
- 367
- References
- 8
- Citations by year
- 2026: 36 · 2025: 44 · 2024: 56 · 2023: 31 · 2022: 43 · 2021: 30 · 2020: 44 · 2019: 31 · 2018: 35 · 2017: 15 · 2016: 1
- FWCI
- 18.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Istanbul Science University (Istanbul Bilim University) (submittedVersion, other-oa)
- Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
- Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
- Funders
- CIDR (X01HG008823)
- Broad Institute Center for Mendelian Disorders (UM1HG008900)
- Yale Center for Mendelian Disorders (U54HG006504)
- Gregory M. Kiez and Mehmet Kutman Foundation
- Italian Ministry of Instruction University and Research (PON01_00937)
- NIH (R01-GM108911)
- NICHD (P01HD070494)
- SFARI (275275)
- FWF (SFB35_3523)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, SLC7A5, branched-chain amino acids, blood-brain barrier, amino acid transport, endothelial cells, mRNA translation, neurological abnormalities, intracerebroventricular administration, motor delay, mouse model
- MeSH terms
- Autism Spectrum Disorder, Amino Acids, Animals, Blood-Brain Barrier, Brain, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Pedigree, Protein Biosynthesis, Mice, Knockout, Large Neutral Amino Acid-Transporter 1, Receptor, TIE-2, Mice
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