Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase
Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase
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DOI：
10.1007/s00439-005-1341-9
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发表时间：
2005-10-01
期刊：
影响因子：
5.3
通讯作者：
Reiss, J
中科院分区：
文献类型：
--
作者：
Leimkühler, S;Charcosset, M;Reiss, J
钼辅因子缺乏症（MIM#252150）是一种严重的常染色体隐性遗传疾病，具有毁灭性的后果。辅因子是涉及四种不同基因（MOCS1，MOCS2，MOCS3和GEPH）的复杂生物合成途径的产物。这种疾病几乎完全由MOCS1或MOCS2基因突变引起。影响该生物合成途径的突变导致致死表型，表现为通过钼辅因子依赖性酶亚硫酸氧化酶失活而导致的进行性神经损伤。在这里，我们描述了MOCS1和MOCS2基因中总共10个新的致病突变。这10个突变中有9个在本质上被归类为致病性的，因为它们产生终止密码子，影响组成性剪接位点位置，或改变严格保守的基序。第十个突变废除MOCS2B基因的终止密码子，从而延长相应的蛋白质。该突变在体外表达，并被发现取消的前体Z和小亚基的阿多巴蝶呤合酶（MOCS2A）的大亚基的结合亲和力的阿多巴蝶呤合酶（MOCS2B）。
Molybdenum cofactor deficiency (MIM#252150) is a severe autosomal- recessive disorder with a devastating outcome. The cofactor is the product of a complex biosynthetic pathway involving four different genes (MOCS1, MOCS2, MOCS3 and GEPH). This disorder is caused almost exclusively by mutations in the MOCS1 or MOCS2 genes. Mutations affecting this biosynthetic pathway result in a lethal phenotype manifested by progressive neurological damage via the inactivation of the molybdenum cofactor-dependent enzyme, sulphite oxidase. Here we describe a total of ten novel disease-causing mutations in the MOCS1 and MOCS2 genes. Nine out of these ten mutations were classified as pathogenic in nature, since they create a stop codon, affect constitutive splice site positions, or change strictly conserved motifs. The tenth mutation abolishes the stop codon of the MOCS2B gene, thus elongating the corresponding protein. The mutation was expressed in vitro and was found to abolish the binding affinities of the large subunit of molybdopterin synthase (MOCS2B) for both precursor Z and the small subunit of molybdopterin synthase (MOCS2A).