ArticleJCI insight2018
Inhibiting neutral amino acid transport for the treatment of phenylketonuria.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 47 citations in OpenAlex.
- Structure-guided development of a potent human BCommunications biology · 2026Article
- Interferon lambda in anti-viral defense and cancer: dual roles, mechanism and therapeutic potential.Journal of translational medicine · 2026Review
- Anesthesia, perimortem conditions, and brain harvest method govern the measured metabolome: analysis of substandard samples generates flawed metabolite levels.Oxford open neuroscience · 2026Article
- Beyond SGLT2: proximal tubule transporters as potential drug targets for chronic kidney disease.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025Review
- Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control.Frontiers in cell and developmental biology · 2025Article
- Structural Dynamics of Neutral Amino Acid Transporter SLC6A19 in Simple and Complex Lipid Bilayers.Journal of cellular biochemistry · 2025Article
- SLC6A19 inhibition facilitates urinary neutral amino acid excretion and lowers plasma phenylalanine.JCI insight · 2024Article
- Molecular basis of inhibition of the amino acid transporter BNature communications · 2024Article
- Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Evaluation of a New Glycomacropeptide-Based Protein Substitute in Powdered and Liquid Format in Patients with PKU.Nutrients · 2023Article
- The SLC6A19 gene mutation in a young man with hyperglycinuria and nephrolithiasis: a case report and literature review.BMC urology · 2022Review
- GPRC6A Mediates Glucose and Amino Acid Homeostasis in Mice.Metabolites · 2022Article
- Physicochemical Characterization and In Vitro Digestibility Study of an In Silico Designed Recombinant Protein Enriched with Large Neutral Amino Acids and Lacking Phenylalanine for Phenylketonuria.The protein journal · 2022Article
- Amino Acid Homeostasis in Mammalian Cells with a Focus on Amino Acid Transport.The Journal of nutrition · 2022Article
- Comparison of Microflow and Analytical Flow Liquid Chromatography Coupled to Mass Spectrometry Global Metabolomics Methods Using a Urea Cycle Disorder Mouse Model.Journal of proteome research · 2022Article
- NADEMBO molecular medicine · 2021Review
- The Adult Phenylketonuria (PKU) Gut Microbiome.Microorganisms · 2021Article
- Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency.Scientific reports · 2021Article
- Opportunities and challenges for antisense oligonucleotide therapies.Journal of inherited metabolic disease · 2021Review
- Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter BFrontiers in pharmacology · 2020Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The neuropathological effects of phenylketonuria (PKU) stem from the inability of the body to metabolize excess phenylalanine (Phe), resulting in accumulation of Phe in the blood and brain. Since the kidney normally reabsorbs circulating amino acids with high efficiency, we hypothesized that preventing the renal uptake of Phe might provide a disposal pathway that could lower systemic Phe levels. SLC6A19 is a neutral amino acid transporter responsible for absorption of the majority of free Phe in the small intestine and reuptake of Phe by renal proximal tubule cells. Transgenic KO mice lacking SLC6A19 have elevated levels of Phe and other amino acids in their urine but are otherwise healthy. Here, we crossed the Pahenu2 mouse model of PKU with the Slc6a19-KO mouse. These mutant/KO mice exhibited abundant excretion of Phe in the urine and an approximately 70% decrease in plasma Phe levels. Importantly, brain Phe levels were decreased by 50%, and the levels of key neurotransmitters were increased in the mutant/KO mice. In addition, a deficit in spatial working memory and markers of neuropathology were corrected. Finally, treatment of Pahenu2 mice with Slc6a19 antisense oligonucleotides lowered Phe levels. The results suggest that inhibition of SLC6A19 may represent a novel approach for the treatment of PKU and related aminoacidopathies.
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