Mitochondrial myopathy and sideroblastic anemia (MLASA) -: Missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation
Mitochondrial myopathy and sideroblastic anemia (MLASA) -: Missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation
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DOI：
10.1074/jbc.m500216200
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发表时间：
2005-05-20
影响因子：
4.8
通讯作者：
Fischel-Ghodsian, N
中科院分区：
文献类型：
--
作者：
Patton, JR;Bykhovskaya, Y;Fischel-Ghodsian, N
PUS1 基因中影响高度保守氨基酸的错义突变与线粒体肌病和铁粒幼细胞贫血 (MLASA) 相关，MLASA 是一种罕见的常染色体隐性遗传氧化磷酸化疾病。 PUS1 基因编码假尿苷合酶 1 (Pus1p)，已知该酶可在其他物种中假尿苷酸化 tRNA。从患者、父母、未受影响的兄弟姐妹和无关对照建立的类淋巴母细胞系中分离总 RNA，并检测 tRNA 在预期位置是否存在假尿苷 (Psi)。来自 MLASA 患者的线粒体和细胞质 tRNA 在通常由 Pus1p 修饰的位点缺乏修饰，而来自对照、未受影响的兄弟姐妹或父母的 tRNA 在这些位置都有 Psi。此外，从 MLASA 患者的细胞系提取的提取物中没有 Pus1p 活性。细胞系中 Pus1p 的免疫组织化学染色显示该蛋白在细胞核、细胞质和线粒体中的分布，并且患者和未受影响的家庭成员之间的染色没有差异。因此，MLASA 与特定位点 tRNA 假尿苷化的缺失或大大减少有关，表明该途径与其分子发病机制有关。
A missense mutation in the PUS1 gene affecting a highly conserved amino acid has been associated with mitochondrial myopathy and sideroblastic anemia (MLASA), a rare autosomal recessive oxidative phosphorylation disorder. The PUS1 gene encodes the enzyme pseudouridine synthase 1 (Pus1p) that is known to pseudouridylate tRNAs in other species. Total RNA was isolated from lymphoblastoid cell lines established from patients, parents, unaffected siblings, and unrelated controls, and the tRNAs were assayed for the presence of pseudouridine (Psi) at the expected positions. Mitochondrial and cytoplasmic tRNAs from MLASA patients are lacking modification at sites normally modified by Pus1p, whereas tRNAs from controls, unaffected siblings, or parents all have Psi at these positions. In addition, there was no Pus1p activity in an extract made from a cell line derived from a patient with MLASA. Immunohistochemical staining of Pus1p in cell lines showed nuclear, cytoplasmic, and mitochondrial distribution of the protein, and there is no difference in staining between patients and unaffected family members. MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis.