title: Slc7a7 disruption causes fetal growth retardation by downregulating Igf1 in the mouse model of lysinuric protein intolerance.
abstract: 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(-/-) 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. 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(-/-) 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.
authors: Dept. of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy.
authors: Maria Pia
authors: MP
authors: Sperandeo
authors: Patrizia
authors: P
authors: Annunziata
authors: Andrea
authors: A
authors: Bozzato
authors: Pasquale
authors: P
authors: Piccolo
authors: Luigi
authors: L
authors: Maiuri
authors: Maria
authors: M
authors: D'Armiento
authors: Andrea
authors: A
authors: Ballabio
authors: Gaetano
authors: G
authors: Corso
authors: Generoso
authors: G
authors: Andria
authors: Giuseppe
authors: G
authors: Borsani
authors: Gianfranco
authors: G
authors: Sebastio
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D027182:Amino Acid Transport System y+ / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D027241:Amino Acid Transport System y+L; D000818:Animals; D001120:Arginine / Q000378:metabolism; D004044:Dietary Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D005838:Genotype; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D014508:Urea / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D004044:Dietary Proteins; C518287:Slc7a7 protein, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D014508:Urea; D001120:Arginine; D008239:Lysine