Lysinuric Protein Intolerance and Associated Pathophysiological Mechanisms

Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder caused by pathogenic variants in the SLC7A7 gene, which encodes the y+LAT1 subunit of the system y+L cationic amino-acid transporter. Loss of functional y+LAT1 impairs uptake and re-absorption of lysine, arginine and ornithine in intestinal and renal epithelia, leading to secondary disruption of the urea cycle and hyperammonemia. Clinical manifestations span failure to thrive, protein-rich food intolerance and multi-organ involvement, notably renal tubulopathy, pulmonary alveolar proteinosis, haematological cytopenias and immune dysregulation. The heterogeneous phenotype arises from cell-type specific expression of the paralogous y+LAT2 transporter, tissue-specific demands for cationic amino acids and downstream effects on signalling pathways. Defective substrate availability in the kidney not only compromises ammonia clearance but also perturbs erythropoietin synthesis, while systemic nutrient shortages influence growth factors such as IGF-1, bone development and immune cell function. Inflammatory complications reflect intrinsic roles of y+LAT1 in macrophage and epithelial cytokine regulation. Current management—based on protein restriction and citrulline supplementation—ameliorates hyperammonemia but fails to prevent many long-term sequelae, underscoring the need for targeted therapies that address both metabolic and non-metabolic facets of the disease.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Lysinuric Protein Intolerance and Associated Pathophysiological Mechanisms publication trend

The graph below shows the total number of articles in lysinuric protein intolerance and associated pathophysiological mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

SLC7A7: Gene encoding the y+LAT1 transporter critical for uptake of dibasic cationic amino acids in epithelial cells.

y+LAT1: Light-chain subunit of system y+L responsible for exchange-mediated transport of lysine, arginine and ornithine.

Urea cycle: Hepatic metabolic pathway that converts ammonia to urea for excretion; dependent on availability of ornithine and citrulline.

Hyperammonemia: Elevated blood ammonia levels resulting from impaired urea cycle function, leading to neurological and systemic toxicity.

Pulmonary alveolar proteinosis: Accumulation of surfactant in alveoli due to defective macrophage-mediated clearance, causing respiratory compromise.

Erythropoietin: Kidney-derived hormone that stimulates red blood cell production; its deficiency leads to anaemia and secondary iron overload.

IGF-1 (Insulin-like Growth Factor 1): Hormone mediating growth and bone development; reduced levels contribute to stunted growth in LPI.

References

1. Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis. Molecular Medicine (2025).
2. Update on Lysinuric Protein Intolerance, a Multi-faceted Disease Retrospective cohort analysis from birth to adulthood. Orphanet Journal of Rare Diseases (2017).
3. Downregulation of SLC7A7 Triggers an Inflammatory Phenotype in Human Macrophages and Airway Epithelial Cells. Frontiers in Immunology (2018).
4. y+LAT1 and y+LAT2 contribution to arginine uptake in different human cell models: Implications in the pathophysiology of Lysinuric Protein Intolerance. Journal of Cellular and Molecular Medicine (2019).
5. Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease. International Journal of Molecular Sciences (2019).
6. Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance. Disease Models & Mechanisms (2023).