RESUMEN
BACKGROUND: Mutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harbouring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations. METHODS: The diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced, and the candidate mutation was analysed in more than 18 000 individuals around the world, its conservation index was estimated in more than 3100 species from protists to mammals, its position was modelled in the crystal structure of a bacteria ortholog subunit, and its functional consequences were studied in a cybrid model. RESULTS: Genetic analysis revealed an m.3472T>C transition in the MT-ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular-genetic analysis and functional studies suggest that this transition is the etiological factor for the disorder. CONCLUSIONS: This mutation expands the spectrum of deleterious changes in mitochondrial DNA-encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients.
Asunto(s)
ADN Mitocondrial/genética , Mitocondrias/genética , NADH Deshidrogenasa/genética , Atrofia Óptica Hereditaria de Leber/genética , Polimorfismo de Nucleótido Simple , Adulto , Secuencia de Bases , Análisis Mutacional de ADN , Humanos , Masculino , Datos de Secuencia Molecular , Atrofia Óptica Hereditaria de Leber/diagnóstico , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Estructura Secundaria de Proteína , Pruebas del Campo Visual , Campos VisualesRESUMEN
Leber's hereditary optic neuropathy is a maternally inherited optic atrophy caused by mitochondrial DNA point mutations. Previous epidemiological studies have shown that individuals from mitochondrial genetic backgrounds (haplogroups) J/Uk and H have a higher and a lower risk, respectively, of suffering this disorder. To analyze the bases of these associations at cellular and molecular levels, functional studies with cybrids provide high quality evidence. Cybrids from haplogroup J contain less mitochondrial deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and synthesize a smaller amount of mitochondrial DNA-encoded polypeptides than those from haplogroup H. Haplogroup J cybrids also display lower oxygen consumption, mitochondrial inner membrane potential and total adenosine-5'-triphosphate (ATP) levels. Moreover, mitochondrial DNA levels correlate with many parameters of the oxidative phosphorylation system. These results suggest that the mitochondrial DNA amount determines oxidative phosphorylation capacity and, along with other recently published observations, support the possibility that mitochondrial DNA levels may be responsible for the bias of the disorder toward males, for the incomplete penetrance of mutations causing Leber's hereditary optic neuropathy and for the association of the disease with particular mitochondrial DNA haplogroups.
Asunto(s)
ADN Mitocondrial/metabolismo , Atrofia Óptica Hereditaria de Leber/metabolismo , Adenosina Trifosfato/metabolismo , Línea Celular Tumoral , ADN Mitocondrial/sangre , ADN Mitocondrial/genética , Haplotipos , Humanos , Potencial de la Membrana Mitocondrial , Proteínas Mitocondriales/biosíntesis , Atrofia Óptica Hereditaria de Leber/sangre , Atrofia Óptica Hereditaria de Leber/genética , Fosforilación Oxidativa , Consumo de Oxígeno , Mutación Puntual , ARN/metabolismo , ARN Mitocondrial , Factores de RiesgoRESUMEN
Mitochondrial diseases, or diseases of the oxidative phosphorylation system, consist of a group of disorders originated by a deficient synthesis of ATP. This system is composed of proteins codified in the two genetic systems of the cell, the nuclear and the mitochondrial genomes, and, therefore, the mode of inheritance could be either mendelian or maternal. The diseases can also appear sporadically. Due to the central role that mitochondria play in cellular physiology, these diseases are a social and health problem of great importance. They are considered rare diseases; however, together they constitute a large variety of genetic disorders. It is also believed that mitochondria are involved, directly or indirectly, in many other human diseases, mainly in age-related diseases. This review will focus mainly on describing the special characteristics of the mitochondrial genetic system and the diseases caused by mitochondrial DNA mutations. We will also note the difficulties in studying these pathologies, and the possible involvement of the genetic variability of the mitochondrial genome in the development of these diseases.
Asunto(s)
Enfermedades Mitocondriales/patología , Fosforilación Oxidativa , ADN Mitocondrial/genética , Humanos , Mitocondrias/genética , Mitocondrias/patología , Herencia Multifactorial/genética , Mutación/genéticaRESUMEN
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