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Cloning of the Causative Gene for Type II Cystinuria

II 型胱氨酸尿症致病基因的克隆

基本信息

批准号：
13470330
负责人：
ITO Haruo
金额：
$ 4.67万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470330/
关键词：
Cystinuria Cystinuria gene R BAT gene BAT1 gene Urinary excretion of cystine Stone recurrence Order-made medicine Gene therapy rBAT遺伝子 BAT2

项目摘要

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.

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。在1999年，我们确定BAT1为非I型胱氨酸尿症的致病基因。BAT 1蛋白是一种约40 kDa的蛋白质，编码487个氨基酸。在人类中，BAT 1 mRNA被证明存在于肾近端小管腔中，功能研究表明，由rBAT和BAT 1基因编码的2种分子是肾小管管腔膜上的二聚体膜蛋白，其功能是胱氨酸转运蛋白。对41例患者的BAT1基因分析检测到7个突变。在2例患者中，没有任何基因突变。35例患者中有31例（约90%）存在BAT 1基因的P482 L（PRO 482 → LEU）错义突变，该突变位于BAT蛋白质胞浆内C端，即终止密码子前6个氨基酸，导致胱氨酸吸收减少。而不是蛋白质本身结构的变化，存在抑制或调节因子结合。这导致管腔细胞膜的分选异常。P482L突变在西方人的遗传分析中尚未报道。这是日本患者胱氨酸尿症的“热点”突变。这些基因突变与临床表现的相关性表明，与非I型胱氨酸尿症患者相比，I型胱氨酸尿症患者的结石复发率和尿胱氨酸排泄量较低。因此，预测疾病严重程度的基因诊断在临床上不仅可用于预防已知病例的结石复发，而且可用于预防无症状携带者的疾病发作。