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.