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

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.

[1]  A. Berdal,et al.  Insulin-like growth factor binding protein (IGFBP-1) involvement in intrauterine growth retardation: study on IGFBP-1 overexpressing transgenic mice. , 2006, Endocrinology.

[2]  G. Parenti,et al.  Growth hormone deficiency in a patient with lysinuric protein intolerance , 2006, European Journal of Pediatrics.

[3]  O. Simell,et al.  Hazards associated with pregnancies and deliveries in lysinuric protein intolerance. , 2006, Metabolism: clinical and experimental.

[4]  C. Duan,et al.  Roles of insulin-like growth factor (IGF) binding proteins in regulating IGF actions. , 2005, General and comparative endocrinology.

[5]  M. P. Sperandeo,et al.  A y+LAT-1 mutant protein interferes with y+LAT-2 activity: implications for the molecular pathogenesis of lysinuric protein intolerance , 2005, European Journal of Human Genetics.

[6]  B. Assael,et al.  Identification of novel mutations in patients with Shwachman‐Diamond syndrome , 2005, Human mutation.

[7]  M. P. Sperandeo,et al.  Lysinuric protein intolerance: identification and functional analysis of mutations of the SLC7A7 gene , 2005, Human mutation.

[8]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[9]  P. Froment,et al.  Insulin-like growth factor binding protein-6 transgenic mice: postnatal growth, brain development, and reproduction abnormalities. , 2004, Endocrinology.

[10]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[11]  G. Van den Berghe,et al.  Regulation of insulin-like growth factor binding protein-1 during protracted critical illness. , 2002, The Journal of clinical endocrinology and metabolism.

[12]  K. Ihara,et al.  Five novel SLC7A7 variants and y+L gene‐expression pattern in cultured lymphoblasts from Japanese patients with lysinuric protein intolerance , 2002, Human Mutation.

[13]  B. Gérard,et al.  Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. , 2002, The New England journal of medicine.

[14]  A. Sinclair,et al.  Rapid DNA extraction and PCR‐sexing of mouse embryos , 2001, Molecular reproduction and development.

[15]  L. Giudice,et al.  Insulin-like growth factor-binding protein-1 in umbilical artery and vein of term fetuses with signs suggestive of distress during labor. , 2001, The Journal of endocrinology.

[16]  G. Borsani,et al.  The molecular bases of cystinuria and lysinuric protein intolerance. , 2001, Current opinion in genetics & development.

[17]  J. Collins,et al.  Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodium-phosphate (Na+-Pi) transporter (SLC34A2). , 1999, Genomics.

[18]  D. Torrents,et al.  Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene , 1999, Nature Genetics.

[19]  G. Borsani,et al.  SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance , 1999, Nature Genetics.

[20]  L. Kühn,et al.  Amino acid transport of y+L‐type by heterodimers of 4F2hc/CD98 and members of the glycoprotein‐associated amino acid transporter family , 1999, The EMBO journal.

[21]  A. Hoeflich,et al.  Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice reduces postnatal body weight gain. , 1999, Endocrinology.

[22]  D. Torrents,et al.  Identification and Characterization of a Membrane Protein (y+L Amino Acid Transporter-1) That Associates with 4F2hc to Encode the Amino Acid Transport Activity y+L , 1998, The Journal of Biological Chemistry.

[23]  R Rizzoli,et al.  Arginine increases insulin-like growth factor-I production and collagen synthesis in osteoblast-like cells. , 1998, Bone.

[24]  Christophe Person,et al.  Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells , 1998, Nature.

[25]  M. Nagao,et al.  [Lysinuric protein intolerance and other cationic aminoacidurias]. , 1998, Ryoikibetsu shokogun shirizu.

[26]  L. Murphy,et al.  Free insulin-like growth factor I (IGF-I) in healthy subjects: relationship with IGF-binding proteins and insulin sensitivity. , 1997, The Journal of clinical endocrinology and metabolism.

[27]  J. Verhaeghe,et al.  C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-1 in cord serum of twins: genetic versus environmental regulation. , 1996, American journal of obstetrics and gynecology.

[28]  M. Takiguchi,et al.  Transcriptional regulation of genes for ornithine cycle enzymes. , 1995, The Biochemical journal.

[29]  L. Powell-Braxton,et al.  IGF-I is required for normal embryonic growth in mice. , 1993, Genes & development.

[30]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[31]  P. Gluckman,et al.  IGF binding protein-2 gene expression and the location of IGF-I and IGF-II in fetal rat lung. , 1992, Development.

[32]  Matthew H. Kaufman,et al.  The Atlas of Mouse Development , 1992 .