Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine

Abstract

Cystinuria is a classic heritable aminoaciduria that involves the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine. Six missense mutations in the human rBAT gene, which is involved in high-affinity transport of cystine and dibasic amino acids in kidney and intestine, segregate with cystinuria. These mutations account for 30% of the cystinuria chromosomes studied. Homozygosity for the most common mutation (M467T) was detected in three cystinuric siblings. Mutation M467T nearly abolished the amino acid transport activity induced by rBAT in Xenopus oocytes. These results establish rBAT as a cystinuria gene.

Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line OK

“…System b o,ϩ is the main, if not the unique, apical transport system involved in the reabsorption of cystine and a major player in dibasic amino acid reabsorption. In the proximal tubule, the heterodimer b o,ϩ AT/rBAT constitutes the apical system b o,ϩ (9), and mutations in either of its subunits resulted in cystinuria (6,10). Cystinuria patients usually show renal cystine reabsorption close to zero, whereas a substantial reabsorption of dibasic amino acids remains active (32).…”

“…First, the heterodimer formed by rBAT and b o,ϩ AT is the amino acid transporter b o,ϩ , which mediates high-affinity uptake of cystine and dibasic amino acids coupled with the efflux of neutral amino acids (5)(6)(7)(8) at the apical membrane of epithelial cells of the proximal tubule (9). Indeed, mutations in the rBAT (SLC3A1) gene cause type I cystinuria, and mutations in the b o,ϩ AT (SLC7A9) gene cause mainly non-type I and also type I cystinuria (recessive inherited aminoacidurias of cystine and dibasic amino acids) (6,10,11). Second, y ϩ LAT-1 dimerizes with 4F2hc to form the amino acid transporter y ϩ L, which mediates the efflux of cationic amino acids coupled with the influx of neutral amino acids plus sodium (12)(13)(14).…”

Electrogenic amino acid exchange via the rBAT transporter

“…Two alternative transcripts (rBAT1 and rBAT2) have been identified for this protein in rabbits, which differ in length and sequence at both 5' and 3' untranslated regions [7]. Defects in this protein have been shown to be associated with cystinuria, suggesting that cystine transport is mediated by this protein in vivo [8]. The clinical importance of this protein warrants further examination of the mechanism of transport mediated by rBAT.…”

Distinct Domains of CD98hc Regulate Integrins and Amino Acid Transport

“…CD98hc overexpression stimulates multiple amino acid transport systems including L, y ϩ L, and x c Ϫ (4). Furthermore, mutations in its closest paralogue, D2 (r-BAT), lead to a disorder of cysteine transport (5). Structurally, CD98 is a disulfidebonded heterodimer of a common ϳ80-kDa heavy chain (CD98hc) with one of several ϳ40-kDa light chains.…”