Department of Biochemistry, Cornell University Medical College, 1300 York Avenue, 10021, New York, New York, USA.
Amino Acids. 1996 Jun;11(2):209-24. doi: 10.1007/BF00813861.
Cystinuria, one of the most common genetic disorders, is characterized by excessive excretion of cystine and basic amino acids in urine. The low solubility of cystine results in formation of kidney stones which can eventually lead to renal failure. Three types of cystinurias have been described. All involve defects in a high-affinity transport system for cystine in the brush border membranes of kidney and intestinal epithelial cells. The molecular properties of proteins involved in epithelial cystine transport are incompletely understood. A protein (NBAT, neutral and basic amino acid transporter), initially cloned by us from rat kidney and shown to be localized in the renal and intestinal brush border membranes, has been implicated in this transport, and mutations in human NBAT gene have been found in several cystinurics, making it a prime candidate for a cystinuria gene. However, mutations in NBAT were found only in Type I cystinurics and not in Types II and III suggesting that defects in other, as yet uncharacterized, genes may also be involved. NBAT has an unusual (for an amino acid transporter) membrane topology. We proposed that the protein contains four membrane-spanning domains, a model disputed by other investigators. We subsequently obtained experimental data consistent with a four membrane-spanning domain model. Furthermore, recently we showed that kidney and intestinal NBAT (85kDa) is associated with another brush border membrane protein (about 50kDa) and have proposed that the heterodimer represents the minimal functional unit of the high-affinity cystine transporter in these membranes. These findings raise the tantalizing possibilities that defects in the NBAT-associated protein might account for cystinurias in individuals with normal NBAT gene (such as the Types II and III cystinurics).
胱氨酸尿症是最常见的遗传疾病之一，其特征是尿液中胱氨酸和碱性氨基酸的排泄过多。由于胱氨酸溶解度低，会形成肾结石，最终导致肾衰竭。已经描述了三种胱氨酸尿症。所有这些都涉及肾脏和肠道上皮细胞刷状缘膜中胱氨酸高亲和力转运系统的缺陷。涉及上皮细胞胱氨酸转运的蛋白质的分子特性尚未完全了解。我们最初从大鼠肾脏中克隆的一种蛋白（NBAT，中性和碱性氨基酸转运蛋白），并证明其定位于肾脏和肠道刷状缘膜中，与这种转运有关，并且在几种胱氨酸尿症患者中发现了人类 NBAT 基因的突变，使其成为胱氨酸尿症基因的主要候选者。然而，NBAT 的突变仅在 I 型胱氨酸尿症患者中发现，而在 II 型和 III 型患者中未发现，这表明其他尚未确定的基因也可能存在缺陷。NBAT 具有不寻常的（对于氨基酸转运蛋白）膜拓扑结构。我们提出该蛋白包含四个跨膜结构域，这一模型受到其他研究人员的质疑。我们随后获得了与四个跨膜结构域模型一致的实验数据。此外，最近我们表明，肾脏和肠道的 NBAT（85kDa）与另一种刷状缘膜蛋白（约 50kDa）相关，并且提出该异源二聚体代表这些膜中高亲和力胱氨酸转运体的最小功能单位。这些发现提出了一个诱人的可能性，即 NBAT 相关蛋白的缺陷可能导致 NBAT 基因正常的个体（如 II 型和 III 型胱氨酸尿症患者）发生胱氨酸尿症。
