Targeted disruption of the murine dihydrolipoamide dehydrogenase gene (Dld) results in perigastrulation lethality

AUTOR(ES)

Johnson, Mark T.

FONTE

The National Academy of Sciences of the USA

RESUMO

The Dld gene product, known as dihydrolipoamide dehydrogenase or the E3 component, catalyzes the oxidation of dihydrolipoyl moieties of four mitochondrial multienzyme complexes: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, branched-chain α-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 Dld gene (Dldtm1mjp). 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.

Documentos Relacionados

• Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality.
• Targeted disruption of the Walker–Warburg syndrome gene Pomt1 in mouse results in embryonic lethality
• Targeted Disruption of the Murine zyxin Gene
• Targeted Disruption of Mouse Yin Yang 1 Transcription Factor Results in Peri-Implantation Lethality
• Targeted disruption of the Rad51 gene leads to lethality in embryonic mice.