Journal Article

<i>Slc7a9</i>-deficient mice develop cystinuria non-I and cystine urolithiasis

Lídia Feliubadaló, María Lourdes Arbonés, Sandra Mañas, Josep Chillarón, Joana Visa, Margot Rodés, Ferran Rousaud, Antonio Zorzano, Manuel Palacín and Virginia Nunes

in Human Molecular Genetics

Volume 12, issue 17, pages 2097-2108
Published in print September 2003 | ISSN: 0964-6906
Published online September 2003 | e-ISSN: 1460-2083 | DOI:
Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis

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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.

Journal Article.  7343 words.  Illustrated.

Subjects: Genetics and Genomics

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