---
_id: '395'
abstract:
- lang: eng
  text: 'Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping
    with other neurological conditions. Despite the remarkable number of scientific
    breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders
    (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great
    challenge. Recent advancements in geno mics, like whole-exome or whole-genome
    sequencing, have enabled scientists to identify numerous mutations underlying
    neurodevelopmental disorders. Given the few hundred risk genes that were discovered,
    the etiological variability and the heterogeneous phenotypic outcomes, the need
    for genotype -along with phenotype- based diagnosis of individual patients becomes
    a requisite. Driven by this rationale, in a previous study our group described
    mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding
    for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause
    of ASD. Following up on the role of BCAAs, in the study described here we show
    that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter
    localized mainly 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 neurolo gical abnormalities. Additionally, deletion of Slc7a5 from
    the neural progenitor cell population leads to microcephaly. Interestingly, we
    demonstrate that BCAA intracerebroventricular administration ameliorates abnormal
    behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients
    diagnosed with neurological dis o r ders helped us identify several patients with
    autistic traits, microcephaly and motor delay carrying deleterious homozygous
    mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological
    syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA
    s in human bra in function. Together with r ecent studies (described in chapter
    two) that have successfully made the transition into clinical practice, our findings
    on the role of B CAAs might have a crucial impact on the development of novel
    individualized therapeutic strategies for ASD. '
acknowledged_ssus:
- _id: PreCl
- _id: EM-Fac
- _id: Bio
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Dora-Clara
  full_name: Tarlungeanu, Dora-Clara
  id: 2ABCE612-F248-11E8-B48F-1D18A9856A87
  last_name: Tarlungeanu
citation:
  ama: Tarlungeanu D-C. The branched chain amino acids in autism spectrum disorders
    . 2018. doi:<a href="https://doi.org/10.15479/AT:ISTA:th_992">10.15479/AT:ISTA:th_992</a>
  apa: Tarlungeanu, D.-C. (2018). <i>The branched chain amino acids in autism spectrum
    disorders </i>. Institute of Science and Technology Austria. <a href="https://doi.org/10.15479/AT:ISTA:th_992">https://doi.org/10.15479/AT:ISTA:th_992</a>
  chicago: Tarlungeanu, Dora-Clara. “The Branched Chain Amino Acids in Autism Spectrum
    Disorders .” Institute of Science and Technology Austria, 2018. <a href="https://doi.org/10.15479/AT:ISTA:th_992">https://doi.org/10.15479/AT:ISTA:th_992</a>.
  ieee: D.-C. Tarlungeanu, “The branched chain amino acids in autism spectrum disorders
    ,” Institute of Science and Technology Austria, 2018.
  ista: Tarlungeanu D-C. 2018. The branched chain amino acids in autism spectrum disorders
    . Institute of Science and Technology Austria.
  mla: Tarlungeanu, Dora-Clara. <i>The Branched Chain Amino Acids in Autism Spectrum
    Disorders </i>. Institute of Science and Technology Austria, 2018, doi:<a href="https://doi.org/10.15479/AT:ISTA:th_992">10.15479/AT:ISTA:th_992</a>.
  short: D.-C. Tarlungeanu, The Branched Chain Amino Acids in Autism Spectrum Disorders
    , Institute of Science and Technology Austria, 2018.
date_created: 2018-12-11T11:46:14Z
date_published: 2018-03-01T00:00:00Z
date_updated: 2023-09-07T12:38:59Z
day: '01'
ddc:
- '570'
- '616'
degree_awarded: PhD
department:
- _id: GaNo
doi: 10.15479/AT:ISTA:th_992
file:
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language:
- iso: eng
month: '03'
oa: 1
oa_version: Published Version
page: '88'
project:
- _id: 25473368-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: F03523
  name: Transmembrane Transporters in Health and Disease
publication_identifier:
  issn:
  - 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
publist_id: '7434'
pubrep_id: '992'
related_material:
  record:
  - id: '1183'
    relation: part_of_dissertation
    status: public
status: public
supervisor:
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
title: 'The branched chain amino acids in autism spectrum disorders '
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2018'
...
---
_id: '634'
abstract:
- lang: eng
  text: As autism spectrum disorder (ASD) is largely regarded as a neurodevelopmental
    condition, long-time consensus was that its hallmark features are irreversible.
    However, several studies from recent years using defined mouse models of ASD have
    provided clear evidence that in mice neurobiological and behavioural alterations
    can be ameliorated or even reversed by genetic restoration or pharmacological
    treatment either before or after symptom onset. Here, we review findings on genetic
    and pharmacological reversibility of phenotypes in mouse models of ASD. Our review
    should give a comprehensive overview on both aspects and encourage future studies
    to better understand the underlying molecular mechanisms that might be translatable
    from animals to humans.
alternative_title:
- ADVSANAT
author:
- first_name: Jan
  full_name: Schroeder, Jan
  last_name: Schroeder
- first_name: Elena
  full_name: Deliu, Elena
  id: 37A40D7E-F248-11E8-B48F-1D18A9856A87
  last_name: Deliu
  orcid: 0000-0002-7370-5293
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
- first_name: Michael
  full_name: Schmeisser, Michael
  last_name: Schmeisser
citation:
  ama: 'Schroeder J, Deliu E, Novarino G, Schmeisser M. Genetic and pharmacological
    reversibility of phenotypes in mouse models of autism spectrum disorder. In: Schmeisser
    M, Boekers T, eds. <i>Translational Anatomy and Cell Biology of Autism Spectrum
    Disorder</i>. Vol 224. Advances in Anatomy Embryology and Cell Biology. Springer;
    2017:189-211. doi:<a href="https://doi.org/10.1007/978-3-319-52498-6_10">10.1007/978-3-319-52498-6_10</a>'
  apa: Schroeder, J., Deliu, E., Novarino, G., &#38; Schmeisser, M. (2017). Genetic
    and pharmacological reversibility of phenotypes in mouse models of autism spectrum
    disorder. In M. Schmeisser &#38; T. Boekers (Eds.), <i>Translational Anatomy and
    Cell Biology of Autism Spectrum Disorder</i> (Vol. 224, pp. 189–211). Springer.
    <a href="https://doi.org/10.1007/978-3-319-52498-6_10">https://doi.org/10.1007/978-3-319-52498-6_10</a>
  chicago: Schroeder, Jan, Elena Deliu, Gaia Novarino, and Michael Schmeisser. “Genetic
    and Pharmacological Reversibility of Phenotypes in Mouse Models of Autism Spectrum
    Disorder.” In <i>Translational Anatomy and Cell Biology of Autism Spectrum Disorder</i>,
    edited by Michael Schmeisser and Tobias Boekers, 224:189–211. Advances in Anatomy
    Embryology and Cell Biology. Springer, 2017. <a href="https://doi.org/10.1007/978-3-319-52498-6_10">https://doi.org/10.1007/978-3-319-52498-6_10</a>.
  ieee: J. Schroeder, E. Deliu, G. Novarino, and M. Schmeisser, “Genetic and pharmacological
    reversibility of phenotypes in mouse models of autism spectrum disorder,” in <i>Translational
    Anatomy and Cell Biology of Autism Spectrum Disorder</i>, vol. 224, M. Schmeisser
    and T. Boekers, Eds. Springer, 2017, pp. 189–211.
  ista: 'Schroeder J, Deliu E, Novarino G, Schmeisser M. 2017.Genetic and pharmacological
    reversibility of phenotypes in mouse models of autism spectrum disorder. In: Translational
    Anatomy and Cell Biology of Autism Spectrum Disorder. ADVSANAT, vol. 224, 189–211.'
  mla: Schroeder, Jan, et al. “Genetic and Pharmacological Reversibility of Phenotypes
    in Mouse Models of Autism Spectrum Disorder.” <i>Translational Anatomy and Cell
    Biology of Autism Spectrum Disorder</i>, edited by Michael Schmeisser and Tobias
    Boekers, vol. 224, Springer, 2017, pp. 189–211, doi:<a href="https://doi.org/10.1007/978-3-319-52498-6_10">10.1007/978-3-319-52498-6_10</a>.
  short: J. Schroeder, E. Deliu, G. Novarino, M. Schmeisser, in:, M. Schmeisser, T.
    Boekers (Eds.), Translational Anatomy and Cell Biology of Autism Spectrum Disorder,
    Springer, 2017, pp. 189–211.
date_created: 2018-12-11T11:47:37Z
date_published: 2017-05-28T00:00:00Z
date_updated: 2021-01-12T08:07:08Z
day: '28'
department:
- _id: GaNo
doi: 10.1007/978-3-319-52498-6_10
editor:
- first_name: Michael
  full_name: Schmeisser, Michael
  last_name: Schmeisser
- first_name: Tobias
  full_name: Boekers, Tobias
  last_name: Boekers
intvolume: '       224'
language:
- iso: eng
month: '05'
oa_version: None
page: 189 - 211
project:
- _id: 25473368-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: F03523
  name: Transmembrane Transporters in Health and Disease
publication: Translational Anatomy and Cell Biology of Autism Spectrum Disorder
publication_identifier:
  eisbn:
  - 978-3-319-52498-6
publication_status: published
publisher: Springer
publist_id: '7156'
quality_controlled: '1'
scopus_import: 1
series_title: Advances in Anatomy Embryology and Cell Biology
status: public
title: Genetic and pharmacological reversibility of phenotypes in mouse models of
  autism spectrum disorder
type: book_chapter
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 224
year: '2017'
...
---
_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. <i>Cell</i>. 2016;167(6):1481-1494.
    doi:<a href="https://doi.org/10.1016/j.cell.2016.11.013">10.1016/j.cell.2016.11.013</a>
  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. <i>Cell</i>. Cell Press. <a href="https://doi.org/10.1016/j.cell.2016.11.013">https://doi.org/10.1016/j.cell.2016.11.013</a>
  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.”
    <i>Cell</i>. Cell Press, 2016. <a href="https://doi.org/10.1016/j.cell.2016.11.013">https://doi.org/10.1016/j.cell.2016.11.013</a>.
  ieee: D.-C. Tarlungeanu <i>et al.</i>, “Impaired amino acid transport at the blood
    brain barrier is a cause of autism spectrum disorder,” <i>Cell</i>, 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.” <i>Cell</i>, vol. 167,
    no. 6, Cell Press, 2016, pp. 1481–94, doi:<a href="https://doi.org/10.1016/j.cell.2016.11.013">10.1016/j.cell.2016.11.013</a>.
  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: 2024-03-25T23:30:07Z
day: '01'
ddc:
- '576'
- '616'
department:
- _id: GaNo
doi: 10.1016/j.cell.2016.11.013
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intvolume: '       167'
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language:
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oa: 1
oa_version: Submitted Version
page: 1481 - 1494
project:
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  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:
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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'
...