Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways
Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways
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DOI：
10.1042/bj20121564
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发表时间：
2013-03-01
影响因子：
4.1
通讯作者：
Scheper, Gert C.
中科院分区：
文献类型：
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作者：
van Berge, Laura;Kevenaar, Josta;Scheper, Gert C.
常染色体隐性遗传性白质病 LBSL（脑干和脊髓受累及乳酸升高的白质脑病）是由编码 mtAspRS（线粒体天冬氨酰-tRNA 合成酶）的 DARS2 突变引起的。一般来说，患者是 DARS2 突变的复合杂合子。在患者中发现了许多不同的突变，包括几种错义突变。在本研究中，我们研究了 LBSL 患者中发现的错义突变对 mtAspRS 的表达、酶活性、定位和二聚化的影响，这对于了解该疾病发病机制背后的细胞缺陷非常重要。对九种不同的错义突变进行了分析，结果显示它们对 mtAspRS 特性有不同的影响。一些突变对酶的催化活性有直接影响；其他对蛋白质表达或二聚化有影响。大多数突变对所研究的 mtAspRS 的至少一项特性有明显影响，可能导致错义变体对细胞中线粒体天冬氨酸化活性的贡献很小。
The autosomal recessive white matter disorder LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is caused by mutations in DARS2, coding for mtAspRS (mitochondrial aspartyl-tRNA synthetase). Generally, patients are compound heterozygous for mutations in DARS2. Many different mutations have been identified in patients, including several missense mutations. In the present study, we have examined the effects of missense mutations found in LBSL patients on the expression, enzyme activity, localization and dimerization of mtAspRS, which is important for understanding the cellular defect underlying the pathogenesis of the disease. Nine different missense mutations were analysed and were shown to have various effects on mtAspRS properties. Several mutations have a direct effect on the catalytic activity of the enzyme; others have an effect on protein expression or dimerization. Most mutations have a clear impact on at least one of the properties of mtAspRS studied, probably resulting in a small contribution of the missense variants to the mitochondrial aspartylation activity in the cell.