Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis

• Published in: Human molecular genetics 2003-09, Vol.12 (17), p.2097-2108
• Main Authors: Feliubadaló, Lídia, Arbonés, María Lourdes, Mañas, Sandra, Chillarón, Josep, Visa, Joana, Rodés, Margot, Rousaud, Ferran, Zorzano, Antonio, Palacín, Manuel, Nunes, Virginia
• Format: Article
• Language: English
• Subjects: Amino Acid Transport Systems, Basic; Amino Acids - metabolism; Aminoacid disorders; Animals; Biological and medical sciences; Carrier Proteins - physiology; Classical genetics, quantitative genetics, hybrids; cystine; Cystine - metabolism; Cystinuria - etiology; Cystinuria - genetics; Cystinuria - pathology; Errors of metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genetics of eukaryotes. Biological and molecular evolution; Heterozygote; Homozygote; Kidney Calculi - pathology; Male; Medical sciences; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - physiology; Metabolic diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Phenotype; rBAT protein; Slc7a9 gene; Tubulopathies; Urinary Calculi - etiology; Urinary Calculi - genetics; Urinary Calculi - pathology; Vertebrata
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddg228

Cystinuria is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in urolithiasis of cystine. Cystinuria is caused by defects in the amino acid transport system b0,+ (i.e. the rBAT/b0,+AT heteromeric complex). Mutations in SLC3A1, encoding rBAT, cause cystinuria type A, characterized by a silent phenotype in heterozygotes (phenotype I). Mutations in SLC7A9, encoding b0,+AT, cause cystinuria type B, in which heterozygotes in most cases hyperexcrete cystine and dibasic amino acids (phenotype non-I). To facilitate in vivo investigation of b0,+AT in cystinuria, Slc7a9 knockout mice have been generated. Expression of b0,+AT protein is completely abolished in the kidney of Slc7a9−/− mice (‘Stones’). In contrast, Stones expressed significant amounts of rBAT protein, which is covalently linked to unidentified light subunit(s). Stones mice present a dramatic hyperexcretion of cystine and dibasic amino acids, while Slc7a9+/− mice show moderate but significant hyperexcretion of these amino acids (phenotype non-I). Forty-two per cent of Stones mice develop cystine calculi in the urinary system. Calculi develop during the first month of life and grow throughout the life span of the animals. Histopathology in kidney reveals typical changes for urolithiasis (tubular and pelvic dilatation, tubular necrosis, tubular hyaline droplets and chronic interstitial nephritis). The fact that some Stones mice, generated in a mixed genetic background, develop cystine calculi from an early age, while others do not develop them in their first year of life, suggests the involvement of modifier genes in the lithiasis phenotype. Thus, Stones provide a valid model of cystinuria which can be used in the study of genetic, pharmacological and environmental factors involved in cystine urolithiasis.