An Animal Model of Type A Cystinuria Due to Spontaneous Mutation in 129S2/SvPasCrl Mice
An Animal Model of Type A Cystinuria Due to Spontaneous Mutation in 129S2/SvPasCrl Mice
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DOI：
10.1371/journal.pone.0102700
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发表时间：
2014-07-21
期刊：
影响因子：
3.7
通讯作者：
Letavernier, Emmanuel
中科院分区：
文献类型：
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作者：
Livrozet, Marine;Vandermeersch, Sophie;Letavernier, Emmanuel
胱氨酸尿症是一种常染色体隐性疾病，由编码rBAT（A型胱氨酸尿症）的SLC 3A 1基因或编码B（0，+）AT（B型胱氨酸尿症）的SLC 7A 9基因突变引起。在这里，我们证明了在一个常用的同源129 S2/SvPasCrl小鼠亚系显着高频率的肾结石，与胱氨酸尿症患者相似。大多数129 S2/SvPasCrl在尿液中表现出特异性胱氨酸晶体，氨基酸尿谱与胱氨酸尿症患者相似。此外，我们观察到一个异质性的炎症浸润和胱氨酸肾小管管型的胱氨酸尿症小鼠的肾脏。与另一种经典小鼠品系C57 BL/6 J小鼠相比，129 S2/SvPasCrl小鼠具有与双侧阻塞性肾积水相关的增加的死亡率。在129 S2/SvPasCrl小鼠中，在近端小管中不存在二元氨基酸四聚体转运蛋白的重亚基rBAT，并且我们在Slc 3a 1基因的高度保守区域中鉴定出单一致病性突变。这种新的小鼠模型模仿人类疾病将使我们能够进一步的病理生理学研究，并可能是有用的，以分析晶体/组织的相互作用在胱氨酸尿症。
Cystinuria is an autosomal recessive disease caused by the mutation of either SLC3A1 gene encoding for rBAT (type A cystinuria) or SLC7A9 gene encoding for b(0,+) AT (type B cystinuria). Here, we evidenced in a commonly used congenic 129S2/SvPasCrl mouse substrain a dramatically high frequency of kidney stones that were similar to those of patients with cystinuria. Most of 129S2/SvPasCrl exhibited pathognomonic cystine crystals in urine and an aminoaciduria profile similar to that of patients with cystinuria. In addition, we observed a heterogeneous inflammatory infiltrate and cystine tubular casts in the kidney of cystinuric mice. As compared to another classical mouse strain, C57BL/6J mice, 129S2/SvPasCrl mice had an increased mortality associated with bilateral obstructive hydronephrosis. In 129S2/SvPasCrl mice, the heavy subunit rBAT of the tetrameric transporter of dibasic amino acids was absent in proximal tubules and we identified a single pathogenic mutation in a highly conserved region of the Slc3a1 gene. This novel mouse model mimicking human disease would allow us further pathophysiological studies and may be useful to analyse the crystal/tissue interactions in cystinuria.