RESUMEN
A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-->A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy.
Asunto(s)
ADN Mitocondrial/genética , Distonía/genética , NAD(P)H Deshidrogenasa (Quinona)/deficiencia , NAD(P)H Deshidrogenasa (Quinona)/genética , NADH Deshidrogenasa/genética , Atrofias Ópticas Hereditarias/genética , Adulto , Secuencia de Aminoácidos , Citrato (si)-Sintasa/metabolismo , Análisis Mutacional de ADN , Distonía/complicaciones , Distonía/enzimología , Transporte de Electrón , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Músculo Esquelético/enzimología , Atrofias Ópticas Hereditarias/complicaciones , Atrofias Ópticas Hereditarias/enzimología , Oxidorreductasas/metabolismo , Linaje , Fenotipo , Mutación Puntual/genéticaRESUMEN
By direct sequencing, we have discovered a novel heteroplasmic mutation (T-->C) at nucleotide position 8993 in the mitochondrial ATPase 6 gene in a family with Leigh's syndrome. Another mutation in the same codon (T8993G) has been reported before in Leigh's syndrome. As these two mutations led to different amino acid substitutions, it provides strong evidence for the relevance of ATP synthase dysfunction in maternally inherited Leigh's syndrome.
Asunto(s)
ADN Mitocondrial/genética , Enfermedad de Leigh/enzimología , Enfermedad de Leigh/genética , Mutación Puntual , ATPasas de Translocación de Protón/genética , Secuencia de Bases , Citosina , ADN Mitocondrial/sangre , ADN Mitocondrial/aislamiento & purificación , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Complejos Multienzimáticos , Oligodesoxirribonucleótidos , Oligonucleótidos Antisentido , Linaje , Reacción en Cadena de la Polimerasa , Mapeo Restrictivo , TiminaRESUMEN
A family with myoclonus epilepsy has been described previously as suffering from an X-linked disorder, because at least four males were affected, and only mild and variable symptoms were seen in some female carriers. In this family, we have now identified a mitochondrial A-->G (8344) heteroplasmic point mutation. This point mutation has been described in families with maternally inherited myoclonus epilepsy and ragged red fibers. The degree of severity of the disorder in the different family members was reflected in the relative quantity of mutated mitochondrial DNA. It is concluded that the mode of inheritance in this family is not X-linked but maternal.
Asunto(s)
ADN Mitocondrial/genética , Epilepsias Mioclónicas/genética , Ligamiento Genético/genética , Mutación Puntual/genética , Cromosoma X , Adenosina , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Guanosina , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
Some microorganisms which are pathogenic in humans share amino acid sequences with human proteins (molecular mimicry). It has been suggested that molecular mimicry might be a reason for autoimmunity as a result of immunological cross reactivity. A homologous sequence of six amino acids has been found in both Klebsiella pneumoniae nitrogenase and the HLA-B27.5 molecule. In addition, (auto)antibodies to a synthetic peptide that contained the HLA-B27.5/klebsiella mimicking epitope have been detected in serum samples from HLA-B27 positive patients with ankylosing spondylitis and Reiter's syndrome. Confirmation of these data is important, because ankylosing spondylitis and Reiter's syndrome have so far been assumed to be 'seronegative' rheumatic diseases. It was, however, not possible to confirm the presence of autoantibodies against the mimicking peptide in serum samples from patients with ankylosing spondylitis and Reiter's syndrome. Serum samples from 81 patients with ankylosing spondylitis, 38 patients with Reiter's syndrome, and 81 healthy blood donors were tested against the 'mimicking peptide' in an enzyme linked immunosorbent assay (ELISA). Some of the serum samples from patients showed high but non-specific binding to the mimicking peptide. A highly significant correlation between binding to plastic coated with the mimicking peptide, to plastic coated with an irrelevant peptide, and even to non-coated plastic was observed. The nature of the serum component(s) in these patient serum samples (and some control serum samples) responsible for the high non-specific binding to plastic remains unclear. It was also shown that antibodies to the HLA-B27 peptide (containing the mimicking epitope) induced in rabbits do not cross react with the klebsiella peptide and vice versa.
Asunto(s)
Artritis Reactiva/inmunología , Autoanticuerpos/análisis , Antígeno HLA-B27/inmunología , Klebsiella pneumoniae/enzimología , Nitrogenasa/inmunología , Péptidos/inmunología , Espondilitis Anquilosante/inmunología , Adulto , Anciano , Animales , Reacciones Cruzadas , Femenino , Antígeno HLA-B27/química , Humanos , Masculino , Persona de Mediana Edad , Nitrogenasa/química , Conejos , Homología de Secuencia de Ácido NucleicoRESUMEN
A patient with the Pearson marrow and pancreas syndrome is presented. She showed an anaemia with neutropenia and thrombopenia, failure to thrive, diarrhoea, disturbed glucose homeostasis and lactic acidosis. An exocrine pancreatic insufficiency was lacking. The disease followed a fatal course. Biochemical investigations of skeletal muscle revealed a disturbed mitochondrial energy metabolism, while many ultrastructural abnormal features were observed in the muscle tissue. Molecular genetic studies showed a de novo deletion in the mitochondrial DNA (mtDNA), different in size from the already published deletions and flanked by two 4 bp direct repeats, interspaced by 4-5 non-repeated nucleotides. mtDNA from 12 other tissues showed the same deletion in different percentages. No obvious relation between these percentages and tissue dysfunction was found. In spite of an open reading frame of 74 codons, only little transcription product of the genomic region resulting from the deletion was found.