Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), 08908 L'Hospitalet de Llobregat, Spain.
Genetics Section, Physiological Sciences Department, Health Sciences and Medicine Faculty, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain.
Int J Mol Sci. 2023 Dec 5;24(24):17140. doi: 10.3390/ijms242417140.
More than 20 years have passed since the identification of and 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 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 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 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.
自 和 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，胱氨酸尿症患者的结石发病年龄、复发和治疗反应存在显著差异，这表明存在影响胱氨酸尿症严重程度的调节因素。2016 年，第二个肾脏胱氨酸转运体，由 基因编码的 AGT1 被发现。尽管它被排除为胱氨酸尿症的致病基因，但它作为调节基因的可能作用仍未被探索。因此，我们在胱氨酸尿症的小鼠模型中分析了它的功能，在 34 名具有不同结石表型的患者中筛选了 基因，并对鉴定出的变体进行了功能表征。小鼠结果表明，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个错义变异体中，有两个表现出 AGT1/rBAT 转运的 25%损伤。然而，在患者中未观察到 基因型和结石表型之间的相关性，这可能是因为这些变体是杂合状态。总之，我们的结果与之前的研究一致，表明 AGT1/rBAT 对胱氨酸尿症患者没有相关影响，尽管不能排除携带纯合致病性变异体的患者的影响。
