Dreumont Natacha, Maresca Antonella, Khandjian Edward W, Baklouti Faouzi, Tanguay Robert M
Laboratory of Cellular and Developmental Genetics, CREFSIP, Department of Medicine, Université Laval, Que., Canada.
Biochem Biophys Res Commun. 2004 Nov 5;324(1):186-92. doi: 10.1016/j.bbrc.2004.09.041.
Messenger RNAs containing premature stop codons are generally targeted for degradation through the nonsense-mediated mRNA decay (NMD) pathway. The subcellular localization of the NMD process in higher eukaryotes remains controversial. While many mRNAs are subjected to NMD prior to their release from the nucleus, a few display cytoplasmic NMD. To understand the possible impact of NMD on the pathogenesis of hereditary tyrosinemia type I, a severe metabolic disease caused by fumarylacetoacetate hydrolase (FAH) deficiency, we examined the metabolism of FAH mRNA harboring a nonsense mutation, W262X, in lymphoblastoid cell lines derived from patients and their parents. W262X-FAH transcripts show a approximately 20-fold reduction in abundance in mutant cells, which is translation-dependent. Cellular fractionation shows that this down-regulation of the W262X transcript occurs in the cytoplasm. Thus, the W262X FAH is another example of nonsense mRNAs subjected to the NMD pathway in the cytoplasm.
含有提前终止密码子的信使核糖核酸（mRNA）通常会通过无义介导的mRNA降解（NMD）途径被靶向降解。在高等真核生物中，NMD过程的亚细胞定位仍存在争议。虽然许多mRNA在从细胞核释放之前就会经历NMD，但也有一些表现出细胞质中的NMD。为了了解NMD对I型遗传性酪氨酸血症发病机制的可能影响，I型遗传性酪氨酸血症是一种由延胡索酰乙酰乙酸水解酶（FAH）缺乏引起的严重代谢疾病，我们在源自患者及其父母的淋巴母细胞系中检测了携带无义突变W262X的FAH mRNA的代谢情况。W262X-FAH转录本在突变细胞中的丰度降低了约20倍，这是依赖翻译的。细胞分级分离显示，W262X转录本的这种下调发生在细胞质中。因此，W262X FAH是细胞质中经历NMD途径的无义mRNA的另一个例子。
