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.

Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc

“…The significance of the neutral amino acid transporter LAT2 in the placental function is still unclear since the homozygous Lat2 gene knockout mice show no apparent phenotypes associated with the defects of placental function (45). In contrast, the knockout of y ϩ LAT1, a transporter for both cationic and neutral amino acids, causes IUGR and highly frequent neonatal lethality (16 of 18 neonates died within 24 h after birth) (46). Although the localization of LAT2 and y ϩ LAT1 in the developing placental tissues has not been investigated in detail, the severe impairment of syncytiotrophoblast formation shown in the present study suggests that at least these other light chains of 4F2hc do not substitute for LAT1 in the placental development in vivo.…”

The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

“…The neutral and dibasic AA exchanger (antiporter) b transporter responsible for cystine reabsorption in the kidney, but transports cationic as well as neutral AAs across the luminal enterocyte membrane (Bertran et al, 1992;Palacin et al, 1998Palacin et al, , 2005Feliubadalo et al, 1999;Pfeiffer et al, 1999;Dave et al, 2004). Among the basolateral enterocyte transporters, the AA exchangers y 1 LAT1-4F2hc and LAT2-4F2hc (SLC7A8-SLC3A2) (Pfeiffer et al, 1999;Rossier et al, 1999;Sperandeo et al, 2007) and the aromatic AA uniporter TAT1 (SLC16A10) (Kim et al, 2001;Quinones et al, 2004;Ramadan et al, 2006Ramadan et al, , 2007Mariotta et al, 2012) were shown to promote accumulation or efflux of AA from the enterocytes to the extracellular space. In addition, the functional interaction between different transporters can affect the net flux of AAs (Nguyen et al, 2007;Ramadan et al, 2007;Verrey et al, 2009).…”

Growth Hormone Deficiency and Lysinuric Protein Intolerance: Case Report and Review of the Literature

“…Nevertheless, Sperandeo et al (Sperandeo et al 2007) reported on the generation of a slc7a7 À/À mice that experienced intrauterine growth restriction (IUGR) by downregulating IGF-1 expression in fetal liver.…”

“…Although studies on slc7a7 À/À mice exclude CAA depletion as a primary cause of IUGR (Sperandeo et al 2007), it is not possible to exclude its role in postnatal growth delay. In fact, it is well known that GH secretion can be promoted by intravenous administration of various AA, and the stimulatory effect of some AA on GH is clinically used as a method to assess the responsiveness of the GH secretory system.…”