RESUMEN
This study aimed to understand the pathogenesis of a new mtDNA-related etiology of Leigh syndrome. We identified the T9176G mutation as the molecular basis of Leigh syndrome in a child and looked for alterations in cellular ATP production. We then modeled the new mtDNA mutation in E. coli and analyzed ATP synthesis, hydrolysis, and the ability of the mutated enzyme to pump protons. Our results suggest that the T9176G change results in a novel, fully assembled enzyme which inhibits the holoenzyme probably by blocking the proton pathway.
Asunto(s)
Adenosina Trifosfatasas/genética , Adenosina Trifosfato/biosíntesis , Adenosina Trifosfato/genética , ADN Mitocondrial/genética , Escherichia coli/genética , Enfermedad de Leigh/genética , Mutación Puntual/genética , Adenosina Trifosfatasas/metabolismo , Encéfalo/enzimología , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Preescolar , Análisis Mutacional de ADN , Transporte de Electrón/genética , Femenino , Genes/genética , Humanos , Enfermedad de Leigh/enzimología , Enfermedad de Leigh/fisiopatología , Modelos Genéticos , Estructura Terciaria de Proteína/genéticaRESUMEN
The role of cell-mediated immunity in the maternal-fetal transmission of Toxoplasma gondii was investigated in 17 pregnant women with primary T. gondii infection, in 7 of whom fetal infection occurred. 18 healthy pregnant women were followed-up as controls. Fetal outcome was uneventful in six women who were treated early in pregnancy with spiramycin, while stillbirth due to T. gondii encephalitis occurred in the offspring of one patient who started with therapy at 34 weeks' gestation. All patients who transmitted T. gondii showed significant changes in the mean levels of immune cells. The most prominent finding was a significantly lower level of natural killer (NK) cells in the mothers transmitting T. gondii to the fetus compared with non-transmitters and controls both in the number (99.7 (71.8-107.5)/microl versus 320.9 (307.9-356.4)/microl and 172.1 (122.4-213.3)/microl: median (25 degrees-75 degrees). p<0.001) and the percentage of NK cells (4.0+/-1.5 per cent versus 13.2+/-2.3 per cent and 10.2+/-3.4 per cent; mean+/-SD, p<0.001). Although limited by the small number of patients, our data suggest that the assessment of NK cells may be considered as a prognostic marker of primary T. gondii infection in pregnancy.