Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorptio n of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, c ause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2) . A gene whose mutation causes non-type I cystinuria has been mapped by lin kage analysis to 19q12-13.1 (refs 3,4). We have identified a new transcript , encoding a protein (b(o,+)AT, for b(o,+) amino acid transporter) belongin g to a family of light subunits of amino acid transporters, expressed in ki dney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of b(o,+)AT and rBA T brings the latter to the plasma membrane, and results in the uptake of L- arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan J ewish patients are homozygous for a founder missense mutation (V170M) that abolishes b(o,+)AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R a nd C295R) and two frameshift (520insT and 596delTG) mutations in other pati ents. Our data establish that mutations in SLC7A9 cause non-type I cystinur ia, and suggest that b(o,+)AT is the light subunit of rBAT.