Targeted disruption of the murine dihydrolipoamide dehydrogenase gene (Dld) results in perigastrulation lethality
Targeted disruption of the murine dihydrolipoamide dehydrogenase gene (Dld) results in perigastrulation lethality
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DOI：
10.1073/pnas.94.26.14512
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发表时间：
1997-12-23
影响因子：
11.1
通讯作者：
Patel, MS
中科院分区：
文献类型：
--
作者：
Johnson, MT;Yang, HS;Patel, MS
Did基因产物，称为二氢硫辛酰胺脱氢酶或E3组分，催化四种线粒体多酶复合物的二氢硫辛酰基部分的氧化：丙酮酸脱氢酶、α-酮戊二酸脱氢酶、支链α-酮酸脱氢酶和甘氨酸裂解系统，人体缺乏E3活性会导致不同程度的神经功能障碍和由支链氨基酸积累引起的有机酸中毒在这项研究中，我们已经引入了一个无效突变到小鼠Did基因（Dld（tm 1 mjp））。杂合子动物的E3和所有受影响的多酶复合物的活性水平约为野生型的一半，但表型正常。相反，Dld（-/-）类动物在妊娠后7.5天死亡，发育明显延迟，随后在妊娠后9.5天发生吸收。Dld（-/-）胚胎在植入子宫壁后不久停止发育，此时大多数胚胎已经开始原肠胚形成。这种无效表型提供了在原肠胚形成期间需要线粒体氧化途径的体内证据。此外，完全缺乏状态的早期产前致死条件可以解释人类中可检测到的E3缺乏病例的低发生率。
The Did gene product, known as dihydrolipoamide dehydrogenase or the E3 component, catalyzes the oxidation of dihydrolipoyl moieties of four mitochondrial multienzyme complexes: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, branched-chain alpha-ketoacid dehydrogenase, and the glycine cleavage system, Deficiency of E3 activity in humans results in various degrees of neurological dysfunction and organic acidosis caused by accumulation of branched chain amino acids and lactic acid, In this study, we have introduced a null mutation into the murine Did gene (Dld(tm1mjp)). The heterozygous animals are shown to have approximately half of wild-type activity levels for E3 and all affected multienzyme complexes but are phenotypically normal, In contrast, the Dld(-/-) class dies prenatally with apparent developmental delay at 7.5 days postcoitum followed by resorption by 9.5 days postcoitum. The Dld(-/-) embryos cease to develop at a time shortly after implantation into the uterine wall when most of the embryos have begun to gastrulate, This null phenotype provides in vivo evidence for the requirement of a mitochondrial oxidative pathway during the perigastrulation period, Furthermore, the early prenatal lethal condition of the complete deficiency state may explain the low incidence of detectable cases of E3 deficiency in humans.