Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis
Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis
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DOI：
10.1093/hmg/ddg228
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Nunes, V
中科院分区：
文献类型：
--
作者：
Feliubadaló, L;Arbonés, ML;Nunes, V
胱氨酸尿症是一种常见的肾重吸收胱氨酸和双碱性氨基酸的隐性疾病，可导致胱氨酸尿石症。胱氨酸尿症是由氨基酸运输系统b(0,+)（即rBAT/b(0,+)AT异构体复合物）的缺陷引起的。编码rBAT的SLC3A1基因突变可导致A型胱氨酸尿症，其特点是杂合子的沉默表型（表型I）。编码b(0,+)AT的SLC7A9突变导致b型胱氨酸尿，在大多数情况下，杂合子高分泌胱氨酸和二碱性氨基酸（表型非i型）。为了便于在体内研究b(0,+) AT在胱氨酸尿中的作用，我们培育了SIc7a9基因敲除小鼠。在Sic7a9（-/-）小鼠的肾脏中，b(0,+)AT蛋白的表达完全消失（'Stones'）。相比之下，Stones表达了大量的rBAT蛋白，该蛋白与未知的光亚基共价连接。结石小鼠表现出胱氨酸和二碱性氨基酸的大量排泄，而Sic7a9（+/-）小鼠表现出适度但显著的这些氨基酸的大量排泄（表型非i型）。42%的结石小鼠在泌尿系统中患上胱氨酸结石。结石在生命的第一个月形成，并在动物的整个生命周期中生长。肾组织病理学显示尿石症的典型变化（肾小管和盆腔扩张、肾小管坏死、肾小管透明液滴和慢性间质性肾炎）。事实上，在混合遗传背景下产生的一些Stones小鼠在很小的时候就会患上胱氨酸结石，而另一些小鼠在出生后的第一年就不会患上胱氨酸结石，这表明修饰基因参与了结石表型。因此，Stones提供了胱氨酸尿石症的有效模型，可用于胱氨酸尿石症的遗传，药理和环境因素的研究。
Cystinuria is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in urolithiasis of cystine. Cystinuria is caused by defects in the amino acid transport system b(0,+) (i.e. the rBAT/b(0,+)AT heteromeric complex). Mutations in SLC3A1, encoding rBAT, cause cystinuria type A, characterized by a silent phenotype in heterozygotes (phenotype I). Mutations in SLC7A9, encoding b(0,+)AT, cause cystinuria type B, in which heterozygotes in most cases hyperexcrete cystine and dibasic amino acids (phenotype non-I). To facilitate in vivo investigation of b(0,+) AT in cystinuria, SIc7a9 knockout mice have been generated. Expression of b(0,+)AT protein is completely abolished in the kidney of Sic7a9(-/-) mice ('Stones'). In contrast, Stones expressed significant amounts of rBAT protein, which is covalently linked to unidentified light subunit(s). Stones mice present a dramatic hyperexcretion of cystine and dibasic amino acids, while Sic7a9(+/-) mice show moderate but significant hyperexcretion of these amino acids (phenotype non-I). Forty-two per cent of Stones mice develop cystine calculi in the urinary system. Calculi develop during the first month of life and grow throughout the life span of the animals. Histopathology in kidney reveals typical changes for urolithiasis (tubular and pelvic dilatation, tubular necrosis, tubular hyaline droplets and chronic interstitial nephritis). The fact that some Stones mice, generated in a mixed genetic background, develop cystine calculi from an early age, while others do not develop them in their first year of life, suggests the involvement of modifier genes in the lithiasis phenotype. Thus, Stones provide a valid model of cystinuria which can be used in the study of genetic, pharmacological and environmental factors involved in cystine urolithiasis.