Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia
Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia
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DOI：
10.1128/mcb.24.2.527-536.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Tsui, LC
中科院分区：
文献类型：
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作者：
Sinasac, DS;Moriyama, M;Tsui, LC
成人发病II型瓜氨酸血症（CTLN2）是一种常染色体隐性遗传病，由SLC25A13基因突变引起，SLC25A13基因编码线粒体天冬氨酸/谷氨酸载体柠檬氨酸。柠檬素的缺乏导致肝脏特异性的精氨酸琥珀酸合成酶（ASS）的定量减少，引起高氨血症和瓜氨酸血症。为了研究柠檬素的生理作用和CTLN2的发展，我们建立了slc25a13敲除（也称为ctrn缺陷）小鼠模型。由此产生的Ctrn（-/-）小鼠缺乏Slc25a13 mRNA和柠檬素蛋白。肝脏线粒体分析显示，天冬氨酸运输和苹果酸-天冬氨酸穿梭的活性明显降低。肝灌注也显示氨的尿生成、乳酸的糖异生和肝细胞内乳酸与丙酮酸比值的增加不足。令人惊讶的是，由于肝脏ASS活性正常，1岁以下的Ctrn（-/-）螨未能表现出ctln2样症状。葡萄糖、氨基酸和氨代谢的血清学测量也没有显示出明显的变化。氮负荷处理只产生肝氨和氨基酸水平的微小变化。这些结果表明，单独的柠檬酸缺乏可能不足以在小鼠中产生ctln2样表型。然而，这些观察结果与CTLN2中出现的可变发病年龄、不完全外显率和强烈的种族偏见是一致的，现在怀疑有其他环境和/或遗传诱因。
Adult-onset type II citrullinemia (CTLN2) is an autosomal recessive disease caused by mutations in SLC25A13, the gene encoding the mitochondrial aspartate/glutamate carrier citrin. The absence of citrin leads to a liver-specific, quantitative decrease of argininosuccinate synthetase (ASS), causing hyperammonemia and citrullinemia. To investigate the physiological role of citrin and the development of CTLN2, an Slc25a13-knockout (also known as Ctrn-deficient) mouse model was created. The resulting Ctrn(-/-) mice were devoid of Slc25a13 mRNA and citrin protein. Liver mitochondrial assays revealed markedly decreased activities in aspartate transport and the malate-aspartate shuttle. Liver perfusion also demonstrated deficits in ureogenesis from ammonia, gluconeogenesis from lactate, and an increase in the lactate-to-pyruvate ratio within hepatocytes. Surprisingly, Ctrn(-/-) mite up to 1 year of age failed to show CTLN2-like symptoms due to normal hepatic ASS activity. Serological measures of glucose, amino acid, and ammonia metabolism also showed no significant alterations. Nitrogen-loading treatments produced only minor changes in the hepatic ammonia and amino acid levels. These results suggest that citrin deficiency alone may not be sufficient to produce a CTLN2-like phenotype in mice. These observations are compatible, however, with the variable age of onset, incomplete penetrance, and strong ethnic bias seen in CTLN2 where additional environmental and/or genetic triggers are now suspected.