Slc7a7 disruption causes fetal growth retardation by down-regulating Igf1 in the mouse model of LPI

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 highthroughput retroviral gene-trapping in embryonic stem cells. The Slc7a7-/- mouse displayed intrauterine growth restriction (IUGR), commonly leading to neonatal lethality. After 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. Insulinlike 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-/- mice. Significant up-regulation or down-regulation (two-fold or greater) was observed for 488 transcripts in intestine, and for 521 transcripts in 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. KEYWORDS: cationic amino acid transport; hyperdibasicaminoaciduria; neonatal lethality. Keywords: Disease state analysis We directly compared Slc7a7 -/- mice versus normal control mice. For liver and intestine tissue, two sets of dye-swap experiments were performed, for a total of four replicate hybridizations for each tissue type.