PDF(Pubmed)
Abstract：
Hydronephrosis, the dilation of kidneys due to abnormal urine retention, occurs spontaneously in certain inbred mouse strains. In humans, its occurrence is often attributed to acquired urinary tract obstructions in adults, whereas in children, it can be congenital. However, the genetic factors underlying hydronephrosis pathogenesis remain unclear. We investigated the cause of hydronephrosis by analyzing tetraspanin 7 (Tspan7) gene-modified mice, which had shown a high incidence of hydronephrosis-like symptoms. We found that these mice were characterized by low liver weights relative to kidney weights and elevated blood ammonia levels, suggesting liver involvement in hydronephrosis. Gene expression analysis of the liver suggested that dysfunction of ornithine transcarbamylase (OTC), encoded by the X chromosome gene Otc and involved in the urea cycle, may contribute as a congenital factor in hydronephrosis. This OTC dysfunction may be caused by genomic mutations in X chromosome genes contiguous to Otc, such as Tspan7, or via the genomic manipulations used to generate transgenic mice, including the introduction of Cre recombinase DNA cassettes and cleavage of loxP by Cre recombinase. Therefore, caution should be exercised in interpreting the hydronephrosis phenotype observed in transgenic mice as solely a physiological function of the target gene.
摘要：
肾积水,由于尿潴留异常引起的肾脏扩张，在某些近交小鼠品系中自发发生。在人类中,它的发生通常归因于成人的获得性尿路阻塞，而在儿童中，它可能是先天性的。然而,肾积水发病的遗传因素尚不清楚。我们通过分析四跨膜蛋白7（Tspan7）基因修饰的小鼠来研究肾积水的原因，这表明肾积水样症状的发生率很高。我们发现这些小鼠的特点是肝脏重量相对于肾脏重量较低，血氨水平升高，提示肝脏受累于肾积水.肝脏的基因表达分析表明鸟氨酸转碳淀粉酶（OTC）功能障碍，由X染色体基因Otc编码并参与尿素循环，可能是肾积水的先天性因素。这种OTC功能障碍可能是由与Otc相邻的X染色体基因中的基因组突变引起的。例如Tspan7，或通过用于产生转基因小鼠的基因组操作，包括Cre重组酶DNA盒的引入和Cre重组酶对loxP的切割。因此,在将转基因小鼠中观察到的肾积水表型解释为仅是靶基因的生理功能时，应谨慎行事。
