RESUMEN
Mitochondrial encephalomyopathies comprise a group of heterogeneous disorders resulting from impaired oxidative phosphorylation (OxPhos). Among a variety of symptoms progressive external ophthalmoplegia (PEO) seems to be the most common. The aim of this study is to present clinical and genetic characteristics of Polish patients with PEO. Clinical, electrophysiological, neuroradiological, and morphological data of 84 patients were analyzed. Genetic studies of mitochondrial DNA (mtDNA) were performed in all patients. Among nuclear DNA (nDNA) genes POLG was sequenced in 41 patients, TWNK (C10orf2) in 13 patients, and RNASEH1 in 2 patients. Total of 27 patients were included in the chronic progressive external ophthalmoplegia (CPEO) group, 24 in the CPEO+ group. Twenty-six patients had mitochondrial encephalomyopathy (ME), six patients Kearns-Sayre syndrome (KSS), and one patient sensory ataxic neuropathy, dysarthria, ophthalmoparesis (SANDO) syndrome. Genetic analysis of nDNA genes revealed the presence of pathogenic or possibly pathogenic variants in the POLG gene in nine patients, the TWNK gene in five patients and the RNASEH1 gene in two patients. Detailed patients' history and careful assessment of family history are essential in the diagnostic work-up. Genetic studies of both mtDNA and nDNA are necessary for the final diagnosis of progressive external ophthalmoplegia and for genetic counseling.
Asunto(s)
ADN Helicasas/genética , ADN Polimerasa gamma/genética , Síndrome de Kearns-Sayre/genética , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Ribonucleasa H/genética , Adolescente , Adulto , Anciano , Cerebelo/diagnóstico por imagen , Cerebelo/metabolismo , Cerebelo/patología , Cerebro/diagnóstico por imagen , Cerebro/metabolismo , Cerebro/patología , Niño , ADN Helicasas/metabolismo , ADN Polimerasa gamma/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Diagnóstico Diferencial , Femenino , Expresión Génica , Humanos , Síndrome de Kearns-Sayre/diagnóstico por imagen , Síndrome de Kearns-Sayre/metabolismo , Síndrome de Kearns-Sayre/patología , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Encefalomiopatías Mitocondriales/diagnóstico por imagen , Encefalomiopatías Mitocondriales/metabolismo , Encefalomiopatías Mitocondriales/patología , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Oftalmoplejía Externa Progresiva Crónica/diagnóstico por imagen , Oftalmoplejía Externa Progresiva Crónica/metabolismo , Oftalmoplejía Externa Progresiva Crónica/patología , Linaje , Polonia , Polimorfismo Genético , Ribonucleasa H/metabolismo , Eliminación de SecuenciaRESUMEN
RNase H1 is able to recognize DNA/RNA heteroduplexes and to degrade their RNA component. As a consequence, it has been implicated in different aspects of mtDNA replication such as primer formation, primer removal, and replication termination, and significant differences have been reported between control and mutant RNASEH1 skin fibroblasts from patients. However, neither mtDNA depletion nor the presence of deletions have been described in skin fibroblasts while still presenting signs of mitochondrial dysfunction (lower mitochondrial membrane potential, reduced oxygen consumption, slow growth in galactose). Here, we show that RNase H1 has an effect on mtDNA transcripts, most likely through the regulation of 7S RNA and other R-loops. The observed effect on both mitochondrial mRNAs and 16S rRNA results in decreased mitochondrial translation and subsequently mitochondrial dysfunction in cells carrying mutations in RNASEH1.
RESUMEN
Mitochondrial diseases are defined by a respiratory chain dysfunction and in most of the cases manifest as multisystem disorders with predominant expression in muscles and nerves and may be caused by mutations in mitochondrial (mtDNA) or nuclear (nDNA) genomes. Most of the proteins involved in respiratory chain function are nuclear encoded, although 13 subunits of respiratory chain complexes (together with 2 rRNAs and 22 tRNAs necessary for their translation) encoded by mtDNA are essential for cell function. nDNA encodes not only respiratory chain subunits but also all the proteins responsible for mtDNA maintenance, especially those involved in replication, as well as other proteins necessary for the transcription and copy number control of this multicopy genome. Mutations in these genes can cause secondary instability of the mitochondrial genome in the form of depletion (decreased number of mtDNA molecules in the cell), vast multiple deletions or accumulation of point mutations which in turn leads to mitochondrial diseases inherited in a Mendelian fashion. The list of genes involved in mitochondrial DNA maintenance is long, and still incomplete.
Asunto(s)
Núcleo Celular/genética , ADN Mitocondrial/genética , Enfermedades Mitocondriales/genética , Transporte de Electrón , Genoma Mitocondrial , Inestabilidad Genómica , Humanos , Mutación PuntualRESUMEN
Mitochondrial diseases are caused by dysfunction of the mitochondrial oxidative phosphorylation system and can be the result of mutations both in mitochondrial DNA and in nuclear DNA. Mitochondrial diseases collectively describe a diverse group of heritable disorders, which may present at any age and have a wide spectrum of clinical manifestations. This leads to highly variable presentations, making the diagnosis of mitochondrial diseases challenging. Recent advances in genetic testing and novel reproductive options hold great promise for improving the clinical identification and treatment of mitochondrial diseases. In this work we discuss what is new in understanding and diagnosis of mitochondrial diseases.