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This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/C191    most recent 00583.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Sperandeo, M. P. Articles by Sebastio, G. Search for Related Content PubMed PubMed Citation Articles by Sperandeo, M. P. Articles by Sebastio, G.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Slc7a7 disruption causes fetal growth retardation by downregulating Igf1 in the mouse model of lysinuric protein intolerance

¹Department of Pediatrics, Federico II University, Naples; ²Sezione di Biologia e Genetica, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Brescia, Brescia; ³Institute of Pediatrics, University of Foggia, Foggia; ⁴Department of Pathology, Federico II University, Naples; ⁵Telethon Institute of Genetics and Medicine, Naples; and ⁶Dipartimento di Scienze Biomediche, Università di Foggia, Foggia, Italy

Submitted 20 November 2006 ; accepted in final form 16 March 2007

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.

cationic amino acid transport; hyperdibasicaminoaciduria; neonatal lethality

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