Abnormalities in the genes that encode Large Amino Acid Transporters increase the risk of Autism Spectrum Disorder.
Adolescent
Adult
Amino Acid Transport System y+
/ genetics
Autism Spectrum Disorder
/ genetics
Cell Line
Child
Child, Preschool
Female
Fusion Regulatory Protein 1, Heavy Chain
/ genetics
Fusion Regulatory Protein 1, Light Chains
/ genetics
Humans
Large Neutral Amino Acid-Transporter 1
/ genetics
Male
Mutation
Tryptophan
/ metabolism
SLC7A5
Autism spectrum disorder (ASD)
amino acids
large amino acid transporter (LAT)
metabolism
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
16
07
2019
revised:
08
10
2019
accepted:
16
10
2019
pubmed:
9
11
2019
medline:
27
3
2021
entrez:
9
11
2019
Statut:
ppublish
Résumé
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder whose molecular mechanisms are largely unknown. Several studies have shown an association between ASD and abnormalities in the metabolism of amino acids, specifically tryptophan and branched-chain amino acids (BCAAs). Ninety-seven patients with ASD were screened by Sanger sequencing the genes encoding the heavy (SLC3A2) and light subunits (SLC7A5 and SLC7A8) of the large amino acid transporters (LAT) 1 and 2. LAT1 and 2 are responsible for the transportation of tryptophan and BCAA across the blood-brain barrier and are expressed both in blood and brain. Functional studies were performed employing the Biolog Phenotype Microarray Mammalian (PM-M) technology to investigate the metabolic profiling in lymphoblastoid cell lines from 43 patients with ASD and 50 controls with particular focus on the amino acid substrates of LATs. We detected nine likely pathogenic variants in 11 of 97 patients (11.3%): three in SLC3A2, three in SLC7A5, and three in SLC7A8. Six variants of unknown significance were detected in eight patients, two of which also carrying a likely pathogenic variant. The functional studies showed a consistently reduced utilization of tryptophan, accompanied by evidence of reduced utilization of other large aromatic amino acids (LAAs), either alone or as part of a dipeptide. Coding variants in the LAT genes were detected in 17 of 97 patients with ASD (17.5%). Metabolic assays indicate that such abnormalities affect the utilization of certain amino acids, particularly tryptophan and other LAAs, with potential consequences on their transport across the blood barrier and their availability during brain development. Therefore, abnormalities in the LAT1 and two transporters are likely associated with an increased risk of developing ASD.
Sections du résumé
BACKGROUND
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder whose molecular mechanisms are largely unknown. Several studies have shown an association between ASD and abnormalities in the metabolism of amino acids, specifically tryptophan and branched-chain amino acids (BCAAs).
METHODS
Ninety-seven patients with ASD were screened by Sanger sequencing the genes encoding the heavy (SLC3A2) and light subunits (SLC7A5 and SLC7A8) of the large amino acid transporters (LAT) 1 and 2. LAT1 and 2 are responsible for the transportation of tryptophan and BCAA across the blood-brain barrier and are expressed both in blood and brain. Functional studies were performed employing the Biolog Phenotype Microarray Mammalian (PM-M) technology to investigate the metabolic profiling in lymphoblastoid cell lines from 43 patients with ASD and 50 controls with particular focus on the amino acid substrates of LATs.
RESULTS
We detected nine likely pathogenic variants in 11 of 97 patients (11.3%): three in SLC3A2, three in SLC7A5, and three in SLC7A8. Six variants of unknown significance were detected in eight patients, two of which also carrying a likely pathogenic variant. The functional studies showed a consistently reduced utilization of tryptophan, accompanied by evidence of reduced utilization of other large aromatic amino acids (LAAs), either alone or as part of a dipeptide.
CONCLUSION
Coding variants in the LAT genes were detected in 17 of 97 patients with ASD (17.5%). Metabolic assays indicate that such abnormalities affect the utilization of certain amino acids, particularly tryptophan and other LAAs, with potential consequences on their transport across the blood barrier and their availability during brain development. Therefore, abnormalities in the LAT1 and two transporters are likely associated with an increased risk of developing ASD.
Identifiants
pubmed: 31701662
doi: 10.1002/mgg3.1036
pmc: PMC6978257
doi:
Substances chimiques
Amino Acid Transport System y+
0
Fusion Regulatory Protein 1, Heavy Chain
0
Fusion Regulatory Protein 1, Light Chains
0
Large Neutral Amino Acid-Transporter 1
0
SLC3A2 protein, human
0
SLC7A5 protein, human
0
SLC7A8 protein, human
0
Tryptophan
8DUH1N11BX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1036Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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