---
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author:
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Dora-Clara
full_name: Tarlungeanu, Dora-Clara
id: 2ABCE612-F248-11E8-B48F-1D18A9856A87
last_name: Tarlungeanu
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Knaus L, Tarlungeanu D-C, Novarino G. S.16.03 A homozygous missense mutation
in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology.
2019;29(Supplement 6):S11. doi:10.1016/j.euroneuro.2019.09.039
apa: Knaus, L., Tarlungeanu, D.-C., & Novarino, G. (2019). S.16.03 A homozygous
missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly.
European Neuropsychopharmacology. Elsevier. https://doi.org/10.1016/j.euroneuro.2019.09.039
chicago: Knaus, Lisa, Dora-Clara Tarlungeanu, and Gaia Novarino. “S.16.03 A Homozygous
Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.”
European Neuropsychopharmacology. Elsevier, 2019. https://doi.org/10.1016/j.euroneuro.2019.09.039.
ieee: L. Knaus, D.-C. Tarlungeanu, and G. Novarino, “S.16.03 A homozygous missense
mutation in SLC7A5 leads to autism spectrum disorder and microcephaly,” European
Neuropsychopharmacology, vol. 29, no. Supplement 6. Elsevier, p. S11, 2019.
ista: Knaus L, Tarlungeanu D-C, Novarino G. 2019. S.16.03 A homozygous missense
mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European
Neuropsychopharmacology. 29(Supplement 6), S11.
mla: Knaus, Lisa, et al. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads
to Autism Spectrum Disorder and Microcephaly.” European Neuropsychopharmacology,
vol. 29, no. Supplement 6, Elsevier, 2019, p. S11, doi:10.1016/j.euroneuro.2019.09.039.
short: L. Knaus, D.-C. Tarlungeanu, G. Novarino, European Neuropsychopharmacology
29 (2019) S11.
date_created: 2020-01-30T10:06:15Z
date_published: 2019-12-13T00:00:00Z
date_updated: 2023-09-07T14:55:23Z
day: '13'
department:
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doi: 10.1016/j.euroneuro.2019.09.039
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issue: Supplement 6
language:
- iso: eng
month: '12'
oa_version: None
page: S11
publication: European Neuropsychopharmacology
publication_identifier:
issn:
- 0924-977X
publication_status: published
publisher: Elsevier
quality_controlled: '1'
status: public
title: S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder
and microcephaly
type: journal_article
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...
---
_id: '5888'
abstract:
- lang: eng
text: "Despite the remarkable number of scientific breakthroughs of the last 100
years, the treatment of neurodevelopmental\r\ndisorders (e.g., autism spectrum
disorder, intellectual disability) remains a great challenge. Recent advancements
in\r\ngenomics, such as whole-exome or whole-genome sequencing, have enabled scientists
to identify numerous\r\nmutations underlying neurodevelopmental disorders. Given
the few hundred risk genes that have been discovered,\r\nthe etiological variability
and the heterogeneous clinical presentation, the need for genotype — along with
phenotype-\r\nbased diagnosis of individual patients has become a requisite. In
this review we look at recent advancements in\r\ngenomic analysis and their translation
into clinical practice."
article_number: '100'
article_processing_charge: No
author:
- first_name: Dora-Clara
full_name: Tarlungeanu, Dora-Clara
id: 2ABCE612-F248-11E8-B48F-1D18A9856A87
last_name: Tarlungeanu
- 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, Novarino G. Genomics in neurodevelopmental disorders: an
avenue to personalized medicine. Experimental & Molecular Medicine.
2018;50(8). doi:10.1038/s12276-018-0129-7'
apa: 'Tarlungeanu, D.-C., & Novarino, G. (2018). Genomics in neurodevelopmental
disorders: an avenue to personalized medicine. Experimental & Molecular
Medicine. Springer Nature. https://doi.org/10.1038/s12276-018-0129-7'
chicago: 'Tarlungeanu, Dora-Clara, and Gaia Novarino. “Genomics in Neurodevelopmental
Disorders: An Avenue to Personalized Medicine.” Experimental & Molecular
Medicine. Springer Nature, 2018. https://doi.org/10.1038/s12276-018-0129-7.'
ieee: 'D.-C. Tarlungeanu and G. Novarino, “Genomics in neurodevelopmental disorders:
an avenue to personalized medicine,” Experimental & Molecular Medicine,
vol. 50, no. 8. Springer Nature, 2018.'
ista: 'Tarlungeanu D-C, Novarino G. 2018. Genomics in neurodevelopmental disorders:
an avenue to personalized medicine. Experimental & Molecular Medicine. 50(8),
100.'
mla: 'Tarlungeanu, Dora-Clara, and Gaia Novarino. “Genomics in Neurodevelopmental
Disorders: An Avenue to Personalized Medicine.” Experimental & Molecular
Medicine, vol. 50, no. 8, 100, Springer Nature, 2018, doi:10.1038/s12276-018-0129-7.'
short: D.-C. Tarlungeanu, G. Novarino, Experimental & Molecular Medicine 50
(2018).
date_created: 2019-01-27T22:59:11Z
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ddc:
- '570'
department:
- _id: GaNo
doi: 10.1038/s12276-018-0129-7
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title: 'Genomics in neurodevelopmental disorders: an avenue to personalized medicine'
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...
---
_id: '395'
abstract:
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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
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citation:
ama: Tarlungeanu D-C. The branched chain amino acids in autism spectrum disorders
. 2018. doi:10.15479/AT:ISTA:th_992
apa: Tarlungeanu, D.-C. (2018). The branched chain amino acids in autism spectrum
disorders . Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th_992
chicago: Tarlungeanu, Dora-Clara. “The Branched Chain Amino Acids in Autism Spectrum
Disorders .” Institute of Science and Technology Austria, 2018. https://doi.org/10.15479/AT:ISTA:th_992.
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. The Branched Chain Amino Acids in Autism Spectrum
Disorders . Institute of Science and Technology Austria, 2018, doi:10.15479/AT:ISTA:th_992.
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
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date_updated: 2023-09-07T12:38:59Z
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call_identifier: FWF
grant_number: F03523
name: Transmembrane Transporters in Health and Disease
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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
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short: CC BY (4.0)
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2018'
...
---
_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
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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.
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title: Impaired amino acid transport at the blood brain barrier is a cause of autism
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