Proteasomal activity and disease outcome in phenylketonuria patients with a structural SLC7A5 variant.

Treatment in phenylketonuria is based on using a diet aimed at protecting the brain from uncontrolled hyperphenylalaninemia. Although treatment methods are well established, clinical outcomes vary among patients. This may be due to alterations of phenylalanine transport mediated by the amino acid transporter LAT1, which also regulates the function of the mTORC1/proteasomal pathway. We investigated the clinical and cellular effects of a structural variant in the SLC7A5 gene, which encodes LAT1. The investigated variant was previously associated with altered phenylalanine metabolism in preliminary studies. We assessed physical and intellectual development in children with phenylketonuria. Next, we explored the cellular mechanisms underlying potential phenotypic differences between carriers and noncarriers of the rs113883650 polymorphism - a marker of the studied SLC7A5 variant. For cellular experiments we used a model of hyperphenylalaninemia based on induced pluripotent stem cells. We assessed LAT1 abundance and performed transcriptomic and proteomic analyses. We found that carriers of rs113883650 were more prone to being overweight but exhibited significantly better intellectual development. They also showed a corresponding increased LAT1 abundance and decreased expression of proteasomal genes and the FOXO signalling pathway. We propose considering of the rs113883650 status during the follow-up of children with phenylketonuria. It may also hold relevance in other LAT1-related conditions including cancers.