Abnormalities in the genes that encode Large Amino Acid Transporters increase the risk of Autism Spectrum Disorder

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.