Paroxysmal non-kinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence
Paroxysmal non-kinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence
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DOI：
10.1093/hmg/ddn441
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发表时间：
2009-03-15
影响因子：
3.5
通讯作者：
Zeviani, Massimo
中科院分区：
文献类型：
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作者：
Ghezzi, Daniele;Viscomi, Carlo;Zeviani, Massimo
阵发性非运动性运动障碍(PNKD)是一种常染色体显性遗传性运动障碍，以肌张力障碍、舞蹈症和手足徐动症发作为特征。肌原纤维生成调节因子-1(MR-1)是PNKD的致病基因，转录成三种选择性剪接形式：长(MR-1L)、中(MR-1M)和小(MR-1S)。此前在MR-1L和MR-1S共同的N端区域发现了两个突变，A7V和A9V。我们现在在同一区域的一名新的PNKD患者中发现了第三个突变，A33P。与以前的报道相反，我们在这里证明了无突变的MR-1M定位于高尔基体、内质网和质膜，而MR-1L和MR-1S亚型都是线粒体蛋白，由于39个氨基酸长的N端线粒体靶向序列(MTS)而被输入细胞器。MTS包含所有三个PNKD突变，然后将成熟蛋白切割出来，然后将其插入线粒体内膜。因此，PNKD患者成熟的MR-1s和MR-1L与正常人完全相同。我们发现野生型和突变型MR-1在进口效率和蛋白质成熟方面没有差异。这些结果表明，PNKD是由于一种基于MTS有害作用的新的疾病机制所致。
Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal-dominant movement disorder characterized by attacks of dystonia, chorea and athetosis. Myofibrillogenesis regulator-1 (MR-1), the gene responsible for PNKD, is transcribed into three alternatively spliced forms: long (MR-1L), medium (MR-1M) and small (MR-1S). Two mutations, A7V and A9V, were previously discovered in the N-terminal region common to MR-1L and MR-1S. We now found a third mutation, A33P, in a new PNKD patient in the same region. Contrary to previous reports, we show here that the mutation-free MR-1M is localized in the Golgi apparatus, ER and plasma membrane, whereas both MR-1L and MR-1S isoforms are mitochondrial proteins, imported into the organelle thanks to a 39 amino acid-long, N-terminal mitochondrial targeting sequence (MTS). The MTS, which contains all three PNKD mutations, is then cleaved off the mature proteins before their insertion in the inner mitochondrial membrane. Therefore, mature MR-1S and MR-1L of PNKD patients are identical to those of normal subjects. We found no difference in import efficiency and protein maturation between wild-type and mutant MR-1 variants. These results indicate that PNKD is due to a novel disease mechanism based on a deleterious action of the MTS.