Mitochondrial DNA Mutations Associated with Neuromuscular Diseases: Analysis and Diagnosis Using the Polymerase Chain Reaction

Wallace, Douglas C.; Lott, Marie T.; Lezza, Angela Maria Serena; Seibel, Peter; Voljavec, Alexander S.; Shoffner, John M.

doi:10.1203/00006450-199011000-00023

Cited by 21 publications

(5 citation statements)

References 19 publications

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“…The causes of rearrangement events are still unclear. It has been proposed that strand slippage during replication of mtDNA molecules leads to deletions in mtDNA [ 16 ], however a new hypothesis suggested that mtDNA deletions are created during the repair of double-stranded mtDNA [ 17 ]. For R-type mtDNA rearrangement, in which two differently oriented mtDNA strands join together, clarification must be sought as to whether replication error is the cause.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Rearrangement Spectrum in Brain Tissue of Alzheimer’s Disease: Analysis of 13 Cases

Chen

Liu²,

Parker

et al. 2016

PLoS ONE

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BackgroundMitochondrial dysfunction may play a central role in the pathologic process of Alzheimer’s disease (AD), but there is still a scarcity of data that directly links the pathology of AD with the alteration of mitochondrial DNA. This study aimed to provide a comprehensive assessment of mtDNA rearrangement events in AD brain tissue.Patients and MethodsPostmortem frozen human brain cerebral cortex samples were obtained from the Banner Sun Health Research Institute Brain and Body Donation Program, Sun City, AZ. Mitochondria were isolated and direct sequence by using MiSeq®, and analyzed by relative software.ResultsThree types of mitochondrial DNA (mtDNA) rearrangements have been seen in post mortem human brain tissue from patients with AD and age matched control. These observed rearrangements include a deletion, F-type rearrangement, and R-type rearrangement. We detected a high level of mtDNA rearrangement in brain tissue from cognitively normal subjects, as well as the patients with Alzheimer's disease (AD). The rate of rearrangements was calculated by dividing the number of positive rearrangements by the coverage depth. The rearrangement rate was significantly higher in AD brain tissue than in control brain tissue (17.9%versus 6.7%; p = 0.0052). Of specific types of rearrangement, deletions were markedly increased in AD (9.2% versus 2.3%; p = 0.0005).ConclusionsOur data showed that failure of mitochondrial DNA in AD brain might be important etiology of AD pathology.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Rearrangement Spectrum in Brain Tissue of Alzheimer’s Disease: Analysis of 13 Cases

Chen

Liu²,

Parker

et al. 2016

PLoS ONE

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“…These include 7 (ND1‐4, 4L, 5, and 6) of the 39 subunits of respiratory complex 1 (reduced nicotinamide adenine dinucleotide‐ubiquinol‐oxidoreductase), 1 (cytochrome b ) of the approximately 10 subunits of respiratory complex III (ubiquinol‐cyto‐chrome‐ c oxidoreductase), 3 (COI, COII, and COIII) of the 13 subunits of respiratory complex IV (cyto‐chrome‐ c oxidase), and 2 (adenosine triphosphate 6 and 8) of the 12 subunits of respiratory complex V (adenosine triphosphate synthase). The remaining subunits of these complexes are encoded by nuclear DNA 7‐9 . The study of mtDNA is easier than the study of genomic DNA because of several unique principles:…”

Section: Introductionmentioning

confidence: 99%

Association of Mitochondrial DNA Deletions and Cochlear Pathology: A Molecular Biologic Tool

et al. 1996

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The purpose of these experiments was to develop a method of isolation, amplification, and identification of cochlear mitochondrial DNA (mtDNA) from minute quantities of tissue. Additionally, studies were designed to detect mtDNA deletions (mtDNA del) from the cochlea that previously have been amplified from other organ systems and tissues. MtDNA del have been associated with many pathologies, including neurological disorders, sensorineural hearing loss, ischemia, cardiomyopathies, and aging. DNA was extracted from rat and human tissues, and polymerase chain reaction was used to amplify mtDNA sequences. A 360 base pair (bp) cytochrome-b gene product and the highly conserved ND1-16S ribosomal ribonucleic acid regions found only in mtDNA were amplified from all tissues. Preliminary studies have identified a 4834 bp mtDNA del in aged rats and a corresponding 4977 bp mtDNA del in aged humans. Additionally, preliminary results in human archival temporal bone studies reveal the presence of the 4977-bp mtDNA deletion in two out of three patients with presbycusis. The deletion was not evident in age-matched control patients without a history of presbycusis. This technique of mtDNA identification makes it possible to investigate specific mtDNA defects from a single cochlea, promoting the study of hereditary hearing loss and presbycusis at a molecular biologic level.

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“…A MERRF (Myoclonic epilepsy with ragged red fibres) é a síndrome mitocondrial mais bem estudada e pode ser causada por mutações em pelo menos dois genes mitocondriais diferentes, mttk e mttl1, que codificam, respectivamente, para RNAs transportadores de lisina e leucina. Defeitos nesses genes resultam em graves defeitos na tradução de genes mitocondriais, causando deficiên-cias na cadeia respiratória celular 13,33 .…”

Section: Epilepsias Idiopáticas Monogênicasunclassified

Genes e epilepsia I: epilepsia e alterações genéticas

Gitaí

Romcy-Pereira²,

Gitaí³

et al. 2008

Rev. Assoc. Med. Bras.

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RESUMOINTRODUÇÃO. Epilepsia é uma desordem neurológica caracterizada por crises espontâneas e recorrentes, que afeta de 2% a 3 % da população mundial. As crises epilépticas refletem atividade elétrica anormal e paroxística, preferencialmente em uma ou várias áreas do córtex cerebral, que podem ser causadas por inúmeras patologias estruturais ou neuroquímicas. Dentre os importantes estudos das últimas décadas no campo da epileptologia, destaca-se a identificação de genes associados a certos tipos de epilepsia. OBJETIVO. Nesta revisão, descrevemos as principais alterações genéticas associadas ao processo epileptogênico, discutindo as mais recentes descobertas e suas contribuições para a compreensão das bases genéticas das epilepsias idiopáticas monogênicas (EIM) e das epilepsias geneticamente complexas. RESULTADOS E CONCLUSÃO. Estudos de ligação e associação mostram que alterações em genes que codificam canais iônicos são as principais causas genéticas das epilepsias idiopáticas monogênicas e de predisposição nas epilepsias geneticamente complexas. Além disso, as síndromes nas quais a epilepsia é um aspecto importante do quadro clínico podem ser provocadas por genes envolvidos em diferentes vias celulares, tais como: migração neuronal, metabolismo de glicogênio e cadeia respiratória. Portanto, acredita-se que diferentes categorias de genes possam atuar na determinação do traço epiléptico. A identificação de tais famílias de genes não apenas nos ajudará a entender as vias moleculares associadas à hiperexcitabilidade neuronal e ao processo epileptogênico, mas também poderá conduzir ao desenvolvimento de novas e mais precisas estratégias de tratamento da epilepsia. UNITERMOS: Mutação. Polimorfismo de nucleotídeo único. SNP. Epilepsia idiopática. Canal iônico. GENES E EPILEPSIA I: EPILEPSIA E ALTERAÇÕES GENÉTICAS INTRODUÇÃOEpilepsia é um tipo de disfunção cerebral caracterizada clinicamente por alterações comportamentais súbitas ("crises epilépticas") que tendem a se repetir ao longo da vida do paciente. Essas crises refletem atividade elétrica anormal e paroxística, acometendo preferencialmente uma ou várias áreas do córtex cerebral e podem ser causadas por inúmeras patologias estruturais ou neuroquímicas 1,2 . Há, portanto, uma diferença entre a definição de epilepsia e de crise epiléptica. Em geral, o diagnóstico de epilepsia implica uma anormalidade epileptogênica persistente do cérebro, provocando crises recorrentes e espontâneas. Em contraposição, pessoas sem epilepsia podem apresentar crise epiléptica provocada por atividade elétrica anormal como resposta isolada do cérebro a um insulto transitório ou a perda de homeostase. Assim, epilepsia presume a existência de uma anormalidade epileptogênica intrínseca, endógena ao próprio cérebro e que está presente mesmo entre as crises, independente de qualquer condição ou insulto agudo. Esta propriedade do "cérebro epiléptico" pode gerar crises recorrentes durante um período de tempo relativamente curto, ou durante muitos anos, ou mesmo durante toda a vida do indivíduo...

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Mitochondrial DNA Mutations Associated with Neuromuscular Diseases: Analysis and Diagnosis Using the Polymerase Chain Reaction

Cited by 21 publications

References 19 publications

Mitochondrial DNA Rearrangement Spectrum in Brain Tissue of Alzheimer’s Disease: Analysis of 13 Cases

Mitochondrial DNA Rearrangement Spectrum in Brain Tissue of Alzheimer’s Disease: Analysis of 13 Cases

Association of Mitochondrial DNA Deletions and Cochlear Pathology: A Molecular Biologic Tool

Genes e epilepsia I: epilepsia e alterações genéticas

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