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The solute carrier family 7A member 7 gene (SLC7A7) encodes the light chain of the heterodimeric carrier responsible for cationic amino acid (CAA) transport across the basolateral membranes of epithelial cells in intestine and kidney. Mutations affecting SLC7A7 cause lysinuric protein intolerance (LPI), a multiorgan disorder with clinical symptoms that include visceromegaly, growth retardation, osteoporosis, hyperammonemia, and hyperdibasicaminoaciduria. Here, we describe the consequences of inactivating Slc7a7 in a mouse model of LPI. The Slc7a7 mutation was generated by high-throughput retroviral gene-trapping in embryonic stem cells. The [Slc7a7.sup.-/-] mouse displayed intrauterine growth restriction (IUGR), commonly leading to neonatal lethality. Alter heavy protein ingestion, the surviving adult animals presented metabolic derangement consistent with that observed in human LPI. IUGR was investigated by examining the expression of main factors controlling fetal growth. Insulin-like growth factor 1, the dominant fetal growth regulator in late gestation, was markedly downregulated as demonstrated by quantitative real-time RT-PCR, immunostaining and Western blot analysis in fetal liver. To further explore the pathophysiology of LPI, gene expression profiling analyses were carried out by DNA microarray technology in intestine and liver of adult [Slc7a7.sup.-/-] mice. Significant upregulation or downregulation (twofold or greater) was observed for 488 transcripts in intestine, and for 521 transcripts in the liver. The largest category of differentially expressed genes corresponds to those involved in transport according to Gene Ontology classification. This mouse model offers new insights into the pathophysiology of LPI and into mechanisms linking CAA metabolic pathways and growth control. cationic amino acid transport: hyperdibasicaminoaciduria; neonatal lethality doi:10.1152/ajpcell.00583.2006

Dall'Asta, Valeria, Ovidio Bussolati, Roberto Sala, Bianca Maria Rotoli, Gianfranco Sebastio, Maria Pia Sperandeo, Generoso Andria, and Gian C. Gazzola. Arginine transport through system [y.sup.+]L in cultured human fibroblasts: normal phenotype of cells from LPI subjects. Am J Physiol Cell Physiol 279: C1829-C1837, 2000.--In lysinuric protein intolerance (LPI), impaired transport of cationic amino acids in kidney and intestine is due to mutations of the SLC7A7 gene. To assess the functional consequences of the LPI defect in nonepithelial cells, we have characterized cationic amino acid (CAA) transport in human fibroblasts obtained from LPI patients and a normal subject. In both cell types the bidirectional fluxes of arginine are due to the additive contributions of two [Na.sup.+]-independent, transstimulated transport systems. One of these mechanisms, inhibited by N-ethylmaleimide (NEM) and sensitive to the membrane potential, is identifiable with system [y.sup.+]. The NEM- and potential-insensitive component, suppressed by L-leucine only in the presence of [Na.sup.+], is mostly due to the activity of system [y.sup.+]L. The inward and outward activities of the two systems are comparable in control and LPI fibroblasts. Both cell types express SLC7A1 (CAT1) and SLC7A2 (CAT2B and CAT2A) as well as SLC7A6 (y+LAT2) and SLC7A7 ([y.sup.+]LAT1). We conclude that LPI fibroblasts exhibit normal CAA transport through system [y.sup.+]L, probably referable to the activity of SLC7A6/y+ LAT2. cationic amino acid; membrane transport; system [y.sup.+]; membrane potential; nitric oxide; lysinuric protein intolerance