A Drosophila model of Barth syndrome.
A Drosophila model of Barth syndrome.
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DOI：
10.1073/pnas.0603242103
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发表时间：
2006-08
影响因子：
11.1
通讯作者：
Yang Xu;Morgan Condell;H. Plesken;Irit Edelman-Novemsky;Jinping Ma;Mindong Ren;M. Schlame
中科院分区：
文献类型：
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作者：
Yang Xu;Morgan Condell;H. Plesken;Irit Edelman-Novemsky;Jinping Ma;Mindong Ren;M. Schlame
巴斯综合征是一种 X 连锁疾病，表现为心肌病和骨骼肌无力。它是由 tafazzin 突变引起的，tafazzin 是一种假定的酰基转移酶，与线粒体磷脂心磷脂代谢的改变有关。为了研究巴斯综合征的分子基础，我们创建了黑腹果蝇突变体，该突变体是由于插入tafazzin基因编码区上游的P元件不精确切除而产生的。正如RNA和蛋白质印迹分析所记录的那样，该突变的纯合果蝇无法表达tafazzin的全长亚型，但仍然存在两个较短的tafazzin转录物，尽管它们编码的蛋白质的表达水平太低而无法通过蛋白质印迹检测到。 tafazzin 突变导致心磷脂减少 80% 及其分子组成多样化，与 Barth 患者中观察到的变化类似。其他磷脂，如磷脂酰胆碱和磷脂酰乙醇胺，不受影响。在飞行和攀爬试验中测量到，带有tafazzin突变的果蝇表现出运动活性降低，并且它们的间接飞行肌肉表现出频繁的线粒体异常，主要是在嵴膜中。因此，果蝇中的tafazzin突变产生了与Barth相关的表型，具有异常心磷脂、病理性线粒体和运动无力的三联征，表明这些发现之间存在因果关系。我们的结论是，全长tafazzin的缺乏是导致心磷脂缺乏的原因，心磷脂缺乏是导致线粒体肌病的疾病机制不可或缺的一部分。
Barth syndrome is an X-linked disease presenting with cardiomyopathy and skeletal muscle weakness. It is caused by mutations in tafazzin, a putative acyl transferase that has been associated with altered metabolism of the mitochondrial phospholipid cardiolipin. To investigate the molecular basis of Barth syndrome, we created Drosophila melanogaster mutants, resulting from imprecise excision of a P element inserted upstream of the coding region of the tafazzin gene. Homozygous flies for that mutation were unable to express the full-length isoform of tafazzin, as documented by RNA and Western blot analysis, but two shorter tafazzin transcripts were still present, although the expression levels of their encoded proteins were too low to be detectable by Western blotting. The tafazzin mutation caused an 80% reduction of cardiolipin and a diversification of its molecular composition, similar to the changes seen in Barth patients. Other phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were not affected. Flies with the tafazzin mutation showed a reduced locomotor activity, measured in flying and climbing assays, and their indirect flight muscles displayed frequent mitochondrial abnormalities, mostly in the cristae membranes. Thus, tafazzin mutations in Drosophila generated a Barth-related phenotype, with the triad of abnormal cardiolipin, pathologic mitochondria, and motor weakness, suggesting causal links between these findings. We conclude that a lack of full-length tafazzin is responsible for the cardiolipin deficiency, which is integral to the disease mechanism, leading to mitochondrial myopathy.