scholarly journals Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

2019 ◽  
Vol 20 (21) ◽  
pp. 5294 ◽  
Author(s):  
Bodoy ◽  
Sotillo ◽  
Espino-Guarch ◽  
Sperandeo ◽  
Ormazabal ◽  
...  
Keyword(s):  
Knockout Mouse ◽  
Failure To Thrive ◽  
Neurological Impairment ◽  
Lysinuric Protein Intolerance ◽  
Metabolic Derangement ◽  
Knockout Mouse Model ◽  
Cationic Amino Acid ◽  
Promising Tool ◽  
Lysinuric Protein ◽  
Protein Intolerance

Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7−/−). The Slc7a7−/− model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7−/− mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7−/− model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.

scholarly journals A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance

2020 ◽  
Vol 29 (13) ◽  
pp. 2171-2184
Author(s):  
Bridget M Stroup ◽  
Ronit Marom ◽  
Xiaohui Li ◽  
Chih-Wei Hsu ◽  
Cheng-Yen Chang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Knockout Mouse ◽  
Skeletal Development ◽  
Growth Failure ◽  
Tubular Dysfunction ◽  
Micro Computed Tomography ◽  
Lysinuric Protein Intolerance ◽  
Knockout Mouse Model ◽  
Lysinuric Protein ◽  
Protein Intolerance

Abstract Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.

scholarly journals The Genetics of Heteromeric Amino Acid Transporters

Physiology ◽  
2005 ◽  
Vol 20 (2) ◽  
pp. 112-124 ◽  
Author(s):  
Manuel Palacín ◽  
Virginia Nunes ◽  
Mariona Font-Llitjós ◽  
Maite Jiménez-Vidal ◽  
Joana Fort ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Mouse Models ◽  
Knockout Mouse ◽  
Amino Acid Transporters ◽  
Lysinuric Protein Intolerance ◽  
Lysinuric Protein ◽  
Recent Developments ◽  
Hartnup Disorder ◽  
Protein Intolerance

Heteromeric amino acid transporters (HATs) are composed of a heavy ( SLC3 family) and a light ( SLC7 family) subunit. Mutations in system b0,+ (rBAT-b0,+AT) and in system y+L (4F2hc-y+LAT1) cause the primary inherited aminoacidurias (PIAs) cystinuria and lysinuric protein intolerance, respectively. Recent developments [including the identification of the first Hartnup disorder gene (B0AT1; SLC6A19)] and knockout mouse models have begun to reveal the basis of renal and intestinal reabsorption of amino acids in mammals.

Lysinuric Protein Intolerance and Hartnup Disease

2016 ◽  
Author(s):  
Gianfranco Sebastio ◽  
Manuel Schiff ◽  
Hélène Ogier de Baulny
Keyword(s):  
Amino Acid ◽  
Renal Disease ◽  
Chronic Renal Disease ◽  
Basolateral Membrane ◽  
Neurological Involvement ◽  
Lysinuric Protein Intolerance ◽  
Cationic Amino Acid ◽  
Transporter Family ◽  
Lysinuric Protein ◽  
Protein Intolerance

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y+LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. Symptoms usually begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, and neurological involvement including hyperammonemic coma will progressively appear. Lung involvement (specifically pulmonary alveolar proteinosis), chronic renal disease that may lead to end stage renal disease, and hemophagocytic lymphohistiocytosis with macrophage activation all represent complications of LPI that may appear at any time from childhood to adulthood. The great variability of the clinical presentation frequently causes misdiagnosis or delayed diagnosis. The basic therapy of LPI consist of a low-protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements.

Arginine transport through system y+L in cultured human fibroblasts: normal phenotype of cells from LPI subjects

2000 ◽  
Vol 279 (6) ◽  
pp. C1829-C1837 ◽  
Author(s):  
Valeria Dall'Asta ◽  
Ovidio Bussolati ◽  
Roberto Sala ◽  
Bianca Maria Rotoli ◽  
Gianfranco Sebastio ◽  
...  
Keyword(s):  
Human Fibroblasts ◽  
Cell Types ◽  
Transport Systems ◽  
Lysinuric Protein Intolerance ◽  
Cationic Amino Acid ◽  
Cultured Human Fibroblasts ◽  
Lysinuric Protein ◽  
Cationic Amino Acids ◽  
Functional Consequences ◽  
Protein Intolerance

In lysinuric protein intolerance (LPI), impaired transport of cationic amino acids in kidney and intestine is due to mutations of the SLC7A7 gene. To assess the functional consequences of the LPI defect in nonepithelial cells, we have characterized cationic amino acid (CAA) transport in human fibroblasts obtained from LPI patients and a normal subject. In both cell types the bidirectional fluxes of arginine are due to the additive contributions of two Na+-independent, transstimulated transport systems. One of these mechanisms, inhibited by N-ethylmaleimide (NEM) and sensitive to the membrane potential, is identifiable with system y+. The NEM- and potential-insensitive component, suppressed by l-leucine only in the presence of Na+, is mostly due to the activity of system y+L. The inward and outward activities of the two systems are comparable in control and LPI fibroblasts. Both cell types express SLC7A1 (CAT1) and SLC7A2 (CAT2B and CAT2A) as well as SLC7A6 (y+LAT2) and SLC7A7 (y+LAT1). We conclude that LPI fibroblasts exhibit normal CAA transport through system y+L, probably referable to the activity of SLC7A6/y+LAT2.

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

2007 ◽  
Vol 293 (1) ◽  
pp. C191-C198 ◽  
Author(s):  
Maria Pia Sperandeo ◽  
Patrizia Annunziata ◽  
Andrea Bozzato ◽  
Pasquale Piccolo ◽  
Luigi Maiuri ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fetal Growth ◽  
Growth Retardation ◽  
Fetal Liver ◽  
Embryonic Stem ◽  
Late Gestation ◽  
Lysinuric Protein Intolerance ◽  
Metabolic Derangement ◽  
Lysinuric Protein ◽  
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.

SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance

10.1038/6815 ◽  
1999 ◽  
Vol 21 (3) ◽  
pp. 297-301 ◽  
Author(s):  
Giuseppe Borsani ◽  
Maria Teresa Bassi ◽  
Maria Pia Sperandeo ◽  
Alessandro De Grandi ◽  
Anna Buoninconti ◽  
...  
Keyword(s):  
Related Protein ◽  
Lysinuric Protein Intolerance ◽  
Lysinuric Protein ◽  
Protein Intolerance
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