PDF(Pubmed)
Abstract：
More than 20 years have passed since the identification of SLC3A1 and SLC7A9 as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the presence of modulatory factors influencing cystinuria severity. In 2016, a second renal cystine transporter, AGT1, encoded by the SLC7A13 gene, was discovered. Although it was discarded as a causative gene for cystinuria, its possible effect as a modulatory gene remains unexplored. Thus, we analyzed its function in mouse models of cystinuria, screened the SLC7A13 gene in 34 patients with different lithiasic phenotypes, and functionally characterized the identified variants. Mice results showed that AGT1/rBAT may have a protective role against cystine lithiasis. In addition, among the four missense variants detected in patients, two exhibited a 25% impairment in AGT1/rBAT transport. However, no correlation between SLC7A13 genotypes and lithiasis phenotypes was observed in patients, probably because these variants were found in heterozygous states. In conclusion, our results, consistent with a previous study, suggest that AGT1/rBAT does not have a relevant effect on cystinuria patients, although an impact in patients carrying homozygous pathogenic variants cannot be discarded.
摘要：
自从SLC3A1和SLC7A9被鉴定为胱氨酸尿症的致病基因以来，已经过去了20多年。然而,膀胱尿症患者在结石发病年龄方面表现出显著的变异性，复发,以及对治疗的反应，提示存在影响胱氨酸尿症严重程度的调节因素。2016年，第二个肾胱氨酸转运蛋白，AGT1，由SLC7A13基因编码，被发现了。尽管它被丢弃为胱氨酸尿症的致病基因，其作为调节基因的可能作用仍有待探索。因此，我们分析了其在胱氨酸尿症小鼠模型中的功能，在34例不同岩性表型患者中筛选SLC7A13基因,并在功能上表征所鉴定的变体。小鼠实验结果表明，AGT1/rBAT可能对胱氨酸结石具有保护作用。此外,在患者中检测到的四种错义变异中，其中2例AGT1/rBAT转运受损25%。然而,在患者中观察到SLC7A13基因型与结石表型之间没有相关性，可能是因为这些变体是在杂合状态中发现的。总之,我们的结果,与之前的研究一致，提示AGT1/rBAT对胱氨酸尿症患者没有相关影响，尽管对携带纯合致病变异的患者的影响不能被丢弃。
