Cloning of the Causative Gene for Type II Cystinuria

1992年，rBAT基因被鉴定为胱氨酸尿症的致病基因。我们在43例I型胱氨酸尿症患者中发现了5个新的rBAT基因突变。1999年，我们发现BAT1基因是非I型胱氨酸尿症的致病基因。BAT1蛋白是一个约40 kDa的蛋白质，编码487个氨基酸。在人类中，BAT1mRNA存在于肾近端小管腔中。功能研究表明，rBAT和BAT1基因编码的两个分子是肾小管上膜上的二聚体膜蛋白，其功能是胱氨酸转运蛋白。对41名患者的BAT1基因分析发现了7个突变。在2例患者中，两种基因均未发生突变。在35例患者中有31例(约90%)检测到BAT1基因P482L(PRO 482对LEU)错义突变，该突变位于BAT蛋白胞浆内C末端，尤其是终止密码子前的6个氨基酸，导致胱氨酸吸收减少。这不是蛋白质本身结构的改变，而是抑制或调节因子的结合。这会导致腔细胞膜的异常分选。在西方人的基因分析中还没有P482L突变的报道。这是日本患者半胱氨酸尿症的一种“热点”突变。临床表现与这些基因突变的相关性表明，与非I型胱氨酸尿症患者相比，I型膀胱氨酸尿症患者的结石复发发生率和尿胱氨酸排泄量均较低。因此，预测疾病严重程度的基因诊断不仅在已知病例中预防结石复发，而且在无症状携带者中预防疾病的发生，在临床上都是有用的。

In 1992, the rBAT gene was identified as a causative gene for cystinuria. We discovered 5 new mutations of the rBAT gene in type I cystinuria in 43 patients. In 1999, we identified BAT1 as a causative gene in non-type I cystinuria. The BAT1 protein is an approximately 40-kDa protein that encodes 487 amino acids. In humans, BAT1 mRNA was shown to be present in the renal proximal tubular lumen.Functional studies suggest that the 2 molecules encoded by the rBAT and BAT1 genes are dimeric membrane proteins on renal tubular luminal membranes that function as cystine transporters. An analysis of the BAT1 gene in 41 patients detected 7 mutations. In 2 patients, there were no mutations of either gene. A high frequency of a P482L (PRO 482 to LEU) missense mutation in the BAT1 gene was detected in 31 of 35 patients (about 90%).This mutation in the intracytoplasmic C terminus of the BAT protein, specifically 6 amino acids before the stop codon, causes a decrease in cystine absorption. Rather than a change in the structure of the protein itself, there is inhibition or regulatory factor binding. This leads to sorting abnormalities to luminal cell membranes. The P482L mutation has not been reported in genetic analysis in Westerners. This is a "hot spot" mutation for cystinuria in Japanese patients. Correlation of clinical findings with these gene mutations shows that patients with type I cystinuria have a lower incidence of stone recurrence and lower urinary excretion of cystine than those with non-type I cystinuria. Therefore, genetic diagnosis to predict discase severity can be clinically useful not only in preventing stone recurrence in known cases, but also in preventing the onset of disease in asymptomatic carriers.