Lysinuric protein intolerance (LPI, MIM 222700) is an inherited aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney, and also intestine. As a consequence, intestinal absorption and renal reabsorption of CAA are impaired. LPI is caused by mutations in the SLC7A7 gene, which encodes y+LAT1 transporter 1. Typically, symptoms begin after weaning with refusal of feeding, vomiting, diarrhea, and consequent failure to thrive. Hepatosplenomegaly, osteoporosis, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features 2. Major complications are immune-like disorders, such as: pulmonary alveolar proteinosis and chronic renal disease, which are increasingly observed in LPI patients 3 without a known pathogenetic mechanism. Because null Slc7a7 mice is lethal 4, we recently generated the ubiquitous and tamoxifen-inducible ablation of Slc7a7 in mouse (Slc7a7 -/-). LPI patients treatment, low-protein diet and citrulline supplementation 5, is needed to maintain Slc7a7-/- mice alive. Under these circumstances (8% of protein in the diet) Slc7a7 -/- mice showed hyperglutaminemia and orotic acid urine excretion suggesting urea cycle dysfunction. As in humans, low arginine and ornithine plasma concentration may be at the basis of the urea cycle dysfunction of LPI mice. Slc7a7 -/- mice, like LPI patients, hyperexcrete cationic (lysine, arginine and ornithine) and some neutral amino acids (e.g. glutamine, alanine). Renal clearance of CAA is increased and also % of tubular reabsorption of Arg, Orn, Lys and some neutral amino acids is reduced. In summary, we have generated the first LPI animal model that allows us to study the mechanisms of pathophysiology of LPI.