Digenic Inheritance in Cystinuria Mouse Model

Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b(0,+), responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b(0,+) AT, cause cystinuria type B. By crossing Slc3a(1-/-) with Slc7a9(-/-) mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months) and late stage (8-months) of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9(+/-)Slc3a1(+/-)) present lower expression of system b(0,+) and higher hyperexcretion of cystine than single heterozygotes (Slc7a9(+/-)Slc3a1(+/+) and Slc7a9(+/+) Slc3a1(+/-)) and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.