Abstract
BackgroundAutism 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).MethodsNinety‐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.ResultsWe 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.ConclusionCoding 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.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by three core signs: impairment of social interactions, communication issues, and repetitive behaviors
The analysis of the metabolic response to individual amino acids indicated moderate differences in the wells containing aromatic amino acids and more drastic ones in the wells containing branched‐chain amino acids (BCAAs) and histidine. These findings suggest that the abnormalities in the large amino acid transporters (LAT) genes reported in this study may affect the metabolism of branch‐chained amino acids and histidine more than aromatic amino acids, which is in line with the observations by Tărlungeanu et al (2016)
The findings indicate that certain heterozygous variants in the LAT genes are sufficient to cause perturbation of the transportation of aromatic amino acids, BCAAs, and, to a lesser extent, histidine
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by three core signs: impairment of social interactions, communication issues, and repetitive behaviors. The combined group of aromatic (tryptophan, phenylalanine, and tyrosine) and branch‐ chained amino acids is defined as large neutral amino acids (LNAAs) Such amino acids play a key role in neurodevelopment and abnormalities in their metabolism may have critical consequences, both because of the perturbation of protein homeostasis (Louros & Osterweil, 2016) and their role as precursors of neuroactive molecules, such as serotonin (Muller, Anacker, & Veenstra‐VanderWeele, 2016). 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. Abnormalities in the LAT1 and two transporters are likely associated with an increased risk of developing ASD
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