Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA)
Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA)
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DOI：
10.1136/jmg.2006.045252
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发表时间：
2007-03-01
影响因子：
4
通讯作者：
Zeviani, Massimo
中科院分区：
文献类型：
--
作者：
Fernandez-Vizarra, Erika;Berardinelli, Angela;Zeviani, Massimo
简介：肌病，乳酸酸中毒和铁粒幼细胞贫血（MLASA）是一种罕见的条件，结合早发性肌病与乳酸酸中毒和铁粒幼细胞贫血。MLASA已与错义突变pseudouridylate合酶1（PUS1），位于细胞核和线粒体中的酶，它将尿苷转化为pseudouridine在几个胞质和线粒体tRNA的位置，并增加蛋白质合成的效率在both compartment.Subjects和方法：我们已经确定了两个意大利兄弟，远亲的后代，他们都受到MLASA。PUS1基因的6个外显子进行了分析，通过自动化sequencing.Results：我们发现合并缺陷的线粒体呼吸链复合物在肌肉和成纤维细胞匀浆的患者，和低水平的mtDNA翻译产物在成纤维细胞线粒体。PUS1（E220X）中存在一种新的纯合终止突变。我们已经研究了PUS1的双重定位的结构和机制方面，证明了位于细胞核中的同种型包含成熟线粒体同种型中不存在的N-末端延伸。PUS1中的终止突变可能决定蛋白质功能的丧失，因为它预测了C端缺失208/427个氨基酸残基的蛋白质的合成，并且与低mtDNA翻译相关。核与线粒体PUS1亚型的结构差异可能与MLASA临床表现的变异性有关。
Introduction: Myopathy, lactic acidosis and sideroblastic anaemia (MLASA) is a rare condition that combines early-onset myopathy with lactic acidosis and sideroblastic anaemia. MLASA has been associated with a missense mutation in pseudouridylate synthase 1 (PUS1), an enzyme located in both nucleus and mitochondria, which converts uridine into pseudouridine in several cytosolic and mitochondrial tRNA positions and increases the efficiency of protein synthesis in both compartments.Subjects and methods: We have identified two Italian brothers, offspring of distantly related parents, both of whom are affected by MLASA. The six exons of the PUS1 gene were analysed by automated sequencing.Results: We found combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria. A novel, homozygous stop mutation was present in PUS1 (E220X). We have investigated the structural and mechanistic aspects of the double localisation of PUS1, demonstrating that the isoform located in the nucleus contains an N-terminal extension which is absent in the mature mitochondrial isoform.Conclusions: The stop mutation in PUS1 is likely to determine the loss of function of the protein, since it predicts the synthesis of a protein missing 208/427 amino acid residues on the C terminus, and was associated with low mtDNA translation. The structural differences in nuclear versus mitochondrial isoforms of PUS1 may be implicated in the variability of the clinical presentations in MLASA.