Molecular basis of hepatic carnitine palmitoyltransferase I deficiency
Molecular basis of hepatic carnitine palmitoyltransferase I deficiency
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DOI：
10.1172/jci2927
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发表时间：
1998-08-01
影响因子：
15.9
通讯作者：
Wanders, RJA
中科院分区：
文献类型：
--
作者：
Ijlst, L;Mandel, H;Wanders, RJA
线粒体脂肪酸β-氧化对于能量产生是重要的，这是由在该途径中发现的不同缺陷所强调的。引起这些缺陷的大多数酶缺陷在蛋白质和基因组水平上都得到了很好的表征。一个例外是肉毒碱棕榈酰转移酶I（CPT I）缺乏症，其中直到现在还没有突变的报道，虽然缺陷是酶的特点。CPT I是肉毒碱依赖性转运穿过线粒体内膜的关键酶，其缺乏导致脂肪酸β-氧化速率降低。在这里，我们报告了一例新病例中肝脏CPT I缺乏症的分子基础的首次描述。cDNA分析显示该患者为错义突变（D454 G）的纯合子。通过在酵母中异源表达来研究所鉴定的突变的影响。表达的突变型CPT IA仅显示表达的野生型CPT IA的活性的2%，表明D454 G突变是致病突变。此外，在患者的成纤维细胞中，CPT IA蛋白在免疫印迹上显著减少，表明突变使蛋白质不稳定。
Mitochondrial fatty acid beta-oxidation is important for energy production, which is stressed by the different defects found in this pathway, Most of the enzyme deficiencies causing these defects are well characterized at both the protein and genomic levels. One exception is carnitine palmitoyltransferase I (CPT I) deficiency, of which until now no mutations have been reported although the defect is enzymatically well characterized. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Here we report the first delineation of the molecular basis of hepatic CPT I deficiency in a new case. cDNA analysis revealed that this patient was homozygous for a missense mutation (D454G), The effect of the identified mutation was investigated by heterologous expression in yeast. The expressed mutant CPT IA displayed only 2% of the activity of the expressed wild-type CPT IA, indicating that the D454G mutation is the disease-causing mutation. Furthermore, in patient's fibroblasts the CPT IA protein was markedly reduced on immunoblot, suggesting that the mutation renders the protein unstable.