RESUMEN
Complex I deficiency is the most frequent cause of respiratory chain diseases. This large multiprotein complex is composed in human of 45 structural subunits, of which 7 are mitochondrial-encoded and 38 are nuclear-encoded. Most of the pathological mutations responsible for complex I deficiencies have been identified to date in complex I structural subunits. Numerous studies from last decade gave some insight into the biogenesis of this huge multi subunit complex of double genetic origin. A sequential incorporation of the structural subunits as well as ten complex I assembly factors has been described. Here, we present a short overview of the human complex I biogenesis and we review the pathological mutations identified to date in eight of the ten known complex I assembly factors.
Asunto(s)
Complejo I de Transporte de Electrón/deficiencia , Complejo I de Transporte de Electrón/genética , Transporte de Electrón/genética , Mitocondrias/enzimología , Enfermedades Mitocondriales/enzimología , Proteínas Nucleares/genética , Estudios de Asociación Genética , Humanos , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutación , Proteínas Nucleares/clasificación , Proteínas Nucleares/metabolismoRESUMEN
Complex I (or NADH-ubiquinone oxidoreductase), is by far the largest respiratory chain complex with 38 subunits nuclearly encoded and 7 subunits encoded by the mitochondrial genome. Its deficiency is the most frequently encountered in mitochondrial disorders. Here, we summarize recent data obtained on architecture of complex I, and review the pathogenic mutations identified to date in nuclear structural complex I genes. The structural NDUFS1, NDUFS2, NDUFV1, and NDUFS4 genes are mutational hot spot genes for isolated complex I deficiency. The majority of the pathogenic mutations are private and the genotype-phenotype correlation is inconsistent in the rare recurrent mutations.
Asunto(s)
Complejo I de Transporte de Electrón/química , Mitocondrias/enzimología , Enfermedades Mitocondriales/enzimología , NADH Deshidrogenasa/metabolismo , Proteínas Nucleares/metabolismo , Transporte de Electrón , Complejo I de Transporte de Electrón/deficiencia , Complejo I de Transporte de Electrón/genética , Estudios de Asociación Genética , Humanos , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Mutación , NADH Deshidrogenasa/genética , Proteínas Nucleares/genéticaRESUMEN
Complex I or reduced nicotinamide adenine dinucleotide (NADH): ubiquinone oxydoreductase deficiency is the most common cause of respiratory chain defects. Molecular bases of complex I deficiencies are rarely identified because of the dual genetic origin of this multi-enzymatic complex (nuclear DNA and mitochondrial DNA) and the lack of phenotype-genotype correlation. We used a rapid method to screen patients with isolated complex I deficiencies for nuclear genes mutations by Surveyor nuclease digestion of cDNAs. Eight complex I nuclear genes, among the most frequently mutated (NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1 and NDUFV2), were studied in 22 cDNA fragments spanning their coding sequences in 8 patients with a biochemically proved complex I deficiency. Single nucleotide polymorphisms and missense mutations were detected in 18.7% of the cDNA fragments by Surveyor nuclease treatment. Molecular defects were detected in 3 patients. Surveyor nuclease screening is a reliable method for genotyping nuclear complex I deficiencies, easy to interpret, and limits the number of sequence reactions. Its use will enhance the possibility of prenatal diagnosis and help us for a better understanding of complex I molecular defects.
