Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction.
Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction.
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DOI：
10.1038/srep42583
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发表时间：
2017-02-15
影响因子：
4.6
通讯作者：
Levtchenko E
中科院分区：
文献类型：
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作者：
Elmonem MA;Khalil R;Khodaparast L;Khodaparast L;Arcolino FO;Morgan J;Pastore A;Tylzanowski P;Ny A;Lowe M;de Witte PA;Baelde HJ;van den Heuvel LP;Levtchenko E
人类普遍存在的蛋白质胱氨酸负责将二硫氨基酸胱氨酸从溶酶体室转运到细胞质中。在人类中，CTNS的致病性突变导致胱氨酸功能缺陷，溶酶体内胱氨酸积累和胱氨酸病的发展。肾脏最初受影响的是广泛性近端肾小管功能障碍（肾范可尼综合征），然后疾病迅速影响肾小球并进展为终末期肾功能衰竭和多器官功能障碍。胱氨酸病的动物模型有限，仅报道了一只Ctns敲除小鼠，显示胱氨酸积累和肾小管功能障碍的晚期迹象，但缺乏肾小球表型。我们建立了一个突变斑马鱼模型，在ctns的第8外显子上有一个纯合无义突变（C .706 C > T; p.Q236X）。胱氨酸突变体幼虫表现出胱氨酸积累，发育迟缓，肾原肾小球和小管功能障碍的迹象，与人类胱氨酸患者的早期表型相似。此外，胱氨酸虫幼虫的凋亡率显著增加，半胱胺（人类胱氨酸消耗疗法）可以改善这种情况。我们的数据表明，ctns基因对斑马鱼肾前足细胞和近端小管功能至关重要，并且ctns突变体可用于研究该病的致病机制和测试胱氨酸病的新疗法。
The human ubiquitous protein cystinosin is responsible for transporting the disulphide amino acid cystine from the lysosomal compartment into the cytosol. In humans, Pathogenic mutations of CTNS lead to defective cystinosin function, intralysosomal cystine accumulation and the development of cystinosis. Kidneys are initially affected with generalized proximal tubular dysfunction (renal Fanconi syndrome), then the disease rapidly affects glomeruli and progresses towards end stage renal failure and multiple organ dysfunction. Animal models of cystinosis are limited, with only a Ctns knockout mouse reported, showing cystine accumulation and late signs of tubular dysfunction but lacking the glomerular phenotype. We established and characterized a mutant zebrafish model with a homozygous nonsense mutation (c.706 C > T; p.Q236X) in exon 8 of ctns. Cystinotic mutant larvae showed cystine accumulation, delayed development, and signs of pronephric glomerular and tubular dysfunction mimicking the early phenotype of human cystinotic patients. Furthermore, cystinotic larvae showed a significantly increased rate of apoptosis that could be ameliorated with cysteamine, the human cystine depleting therapy. Our data demonstrate that, ctns gene is essential for zebrafish pronephric podocyte and proximal tubular function and that the ctns-mutant can be used for studying the disease pathogenic mechanisms and for testing novel therapies for cystinosis.