Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)
Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)
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DOI：
10.1086/421530
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发表时间：
2004-06-01
影响因子：
9.8
通讯作者：
Fischel-Ghodsian, N
中科院分区：
文献类型：
--
作者：
Bykhovskaya, Y;Casas, K;Fischel-Ghodsian, N
线粒体肌病和铁粒幼细胞性贫血（MLASA）是一种罕见的，常染色体隐性氧化磷酸化障碍，特异性骨骼肌和骨髓。对两个MLASA家系进行连锁分析和纯合性检测，将候选区域定位在12q24.33的1.2 Mb处。对该区域6个已知基因以及4个在骨髓或肌肉中表达的推定基因进行序列分析，发现这些家族中所有MLASA患者的假尿苷合酶1基因（PUS1）均存在纯合错义突变。该突变是这10个基因中唯一不是已知多态性的氨基酸编码变化，并且在934个对照中未发现。氨基酸的变化影响了一个高度保守的氨基酸，似乎是在蛋白质的催化中心，PUS1p。PUS1广泛表达，并且来自肝脏、脑、心脏、骨髓和骨骼肌的RNA的定量表达分析显示骨骼肌和脑中的表达水平升高。我们提出线粒体tRNA的假尿苷酸化缺陷是MLASA的病因之一。在这些家庭中的突变的病理生理途径的鉴定可能揭示氧化磷酸化障碍的组织特异性。
Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Linkage analysis and homozygosity testing of two families with MLASA localized the candidate region to 1.2 Mb on 12q24.33. Sequence analysis of each of the six known genes in this region, as well as four putative genes with expression in bone marrow or muscle, identified a homozygous missense mutation in the pseudouridine synthase 1 gene (PUS1) in all patients with MLASA from these families. The mutation is the only amino acid coding change in these 10 genes that is not a known polymorphism, and it is not found in 934 controls. The amino acid change affects a highly conserved amino acid, and appears to be in the catalytic center of the protein, PUS1p. PUS1 is widely expressed, and quantitative expression analysis of RNAs from liver, brain, heart, bone marrow, and skeletal muscle showed elevated levels of expression in skeletal muscle and brain. We propose deficient pseudouridylation of mitochondrial tRNAs as an etiology of MLASA. Identification of the pathophysiologic pathways of the mutation in these families may shed light on the tissue specificity of oxidative phosphorylation disorders.