Basic concepts of medical genetics, pathogenetics, part 3 (original) (raw)
Mitochondrial DNA mutations in human disease
Biochimica Et Biophysica Acta-bioenergetics, 2001
The small, maternally inherited mitochondrial DNA (mtDNA) has turned out to be a Pandora's box of pathogenic mutations: 13 years into the era of “molecular mitochondrial medicine,” more than 100 pathogenic point mutations and innumerable rearrangements have been associated with a striking variety of multisystemic as well as tissue-specific human diseases. After reviewing the principles of mitochondrial genetics, we consider disorders due to mutations in genes affecting mitochondrial protein synthesis and disorders due to mutations in protein-coding genes. In contrast to the remarkable progress in our understanding of etiology, pathogenesis is only partially explained by the rules of mitochondrial genetics and remains largely unclear. We review recent progress in prenatal diagnosis, epidemiology, and in the development of animal models harboring mtDNA mutations. © 2001 Wiley-Liss, Inc.
Mitochondrial Mutational Spectra in Human Cells and Tissues
Proceedings of The National Academy of Sciences, 1997
We have found that human organs such as colon, lung, and muscle, as well as their derived tumors, share nearly all mitochondrial hotspot point mutations. Seventeen hotspots, primarily G 3 A and A 3 G transitions, have been identified in the mitochondrial sequence of base pairs 10,030-
Human Mitochondrial DNA: Particularities and Diseases
2021
Mitochondria are the cell’s power site, transforming energy into a form that the cell can employ for necessary metabolic reactions. These organelles present their own DNA. Although it codes for a small number of genes, mutations in mtDNA are common. Molecular genetics diagnosis allows the analysis of DNA in several areas such as infectiology, oncology, human genetics and personalized medicine. Knowing that the mitochondrial DNA is subject to several mutations which have a direct impact on the metabolism of the mitochondrion leading to many diseases, it is therefore necessary to detect these mutations in the patients involved. To date numerous mitochondrial mutations have been described in humans, permitting confirmation of clinical diagnosis, in addition to a better management of the patients. Therefore, different techniques are employed to study the presence or absence of mitochondrial mutations. However, new mutations are discovered, and to determine if they are the cause of disea...
The Journal of Pathology, 2012
The small circle of mitochondrial DNA (mtDNA) present in all human cells has proven to be a veritable Pandora's box of pathogenic mutations and rearrangements. In this review, we summarize the distinctive rules of mitochondrial genetics (maternal inheritance, mitotic segregation, heteroplasmy and threshold effect), stress the relatively high prevalence of mtDNA-related diseases, and consider recent additions to the already long list of pathogenic mutations (especially mutations affecting protein-coding genes). We then discuss more controversial issues, including the functional or pathological role of mtDNA haplotypes, the pathogenicity of homoplasmic mutations and the still largely obscure pathophysiology of mtDNA mutations.
Brain, 2004
In the medical literature the term 'mitochondrial disorders' is to a large extent applied to the clinical syndromes associated with abnormalities of the common final pathway of mitochondrial energy metabolism, i.e. oxidative phosphorylation (OXPHOS). Faulty oxidative phosphorylation may be due to overall dysfunction of the respiratory chain, a heteromultimeric structure embedded in the inner mitochondrial membrane, or can be associated with single or multiple defects of the five complexes forming the respiratory chain itself. From the genetic standpoint, the respiratory chain is a unique structure of the inner mitochondrial membrane formed by means of the complementation of two separate genetic systems: the nuclear genome and the mitochondrial genome. The nuclear genome encodes the large majority of the protein subunits of the respiratorycomplexes andmost ofthe mitochondrial DNA (mtDNA) replication and expression systems, whereas the mitochondrial genome encodes only 13 respiratory complex subunits, and some RNA components of the mitochondrial translational apparatus. Accordingly, mitochondrial disorders due to defects in OXPHOS include both mendelianinherited and cytoplasmic-inherited diseases. This review describes human genetic diseases associated with mtDNA and nuclear DNA mutations leading to impaired OXPHOS.
n this research, we aimed to study the clinical findings in a group of 28 Egyptian patients with suspected mitochondrial disease and to test whether seven common mitochondrial DNA (mtDNA) mutations causing mitochondrial disorders in different populations are the same ones causing mutations in Egyptian patients. Twenty-eight Egyptian patients with suspected mtDNA disorders were subjected to a thorough clinical examination, pedigree analysis, and biochemical investigations. Neurophysiologic investigations were carried out including electroencephalogram, electromyelogram, nerve conduction velocities, a complete eye evaluation including electroretinogram and visual-evoked potential, a hearing test, brain MRI, and magnetic resonance spectroscopy. Pathological examination on muscle biopsy stained by the modified Gomori trichrome stain was also carried out. PCR-RFLP analyses were carried out for the detection of seven (3243A4G, 3271T4C, 8334A4G, 8993T4G/C, 3256C4T, 4332G4A, and 12147G4A) mtDNA point mutations. All 28 patients showed variable multisystem affection. We divided the patients into three groups according to the main findings and investigations. Group 1 included four patients with suspected Leigh’s syndrome, group 2 included two patients with suspected MELAS, and group 3 included 22 patients with suspected general mitochondrial disorder. The molecular study indicated that the chosen point mutations (3243A4G, 3271T4C, 8334A4G, 8993T4G/C, 3256C4T, 4332G4A, and 12147G4A) were not detected in this group of Egyptian patients. The presence of other different mutations in either the nuclear or the mitochondrial genomes might be the reason for the negative results obtained in this research. Further confirmation by sequencing of mitochondrial and genomic genes is recommended.
Techniques and Pitfalls in the Detection of Pathogenic Mitochondrial DNA Mutations
Journal of Molecular Diagnostics, 2003
Mutations in the mitochondrial DNA (mtDNA) are now recognized as major contributors to human pathologies and possibly to normal aging. A large number of rearrangements and point mutations in protein coding and tRNA genes have been identified in patients with mitochondrial disorders. In this review, we discuss genotype-phenotype correlations in mitochondrial diseases and common techniques used to identify pathogenic mtDNA mutations in human tissues. Although most of these approaches employ standard molecular biology tools , the co-existence of wild-type and mutated mtDNA (mtDNA heteroplasmy) in diseased tissues complicates both the detection and accurate determination of the size of the mutated fractions. To address these problems , novel approaches were developed and are discussed in this review. (J Mol Diagn 2003, 5:197-208)
Mitochondrial diseases caused by mtDNA mutations: a mini-review
Therapeutics and Clinical Risk Management
There are several types of mitochondrial cytopathies, which cause a set of disorders, arise as a result of mitochondria's failure. Mitochondria's functional disruption leads to development of physical, growing and cognitive disabilities and includes multiple organ pathologies, essentially disturbing the nervous and muscular systems. The origins of mitochondrial cytopathies are mutations in genes of nuclear DNA encoding mitochondrial proteins or in mitochondrial DNA. Nowadays, numerous mtDNA mutations significant to the appearance and progress of pathologies in humans are detected. In this mini-review, we accent on the mitochondrial cytopathies related to mutations of mtDNA. As well known, there are definite set of symptoms of mitochondrial cytopathies distinguishing or similar for different syndromes. The present article contains data about mutations linked with cytopathies that facilitate diagnosis of different syndromes by using genetic analysis methods. In addition, for every individual, more effective therapeutic approach could be developed after wide-range mutant background analysis of mitochondrial genome.
The Pathophysiology of Mitochondrial Biogenesis: Towards Four Decades of Mitochondrial DNA Research
Molecular Genetics and Metabolism, 2000
Mitochondria are with very few exceptions ubiquitous organelles in eukaryotic cells where they are essential for cell life and death. Mitochondria play a central role not only in a variety of metabolic pathways including the supply of the bulk of cellular ATP through oxidative phosphorylation (OXPHOS), but also in complex processes such as development, apoptosis, and aging. Mitochondria contain their own genome that is replicated and expressed within the organelle. It encodes 13 polypeptides all of them components of the OXPHOS system, and thus, the integrity of the mitochondrial DNA (mtDNA) is critical for cellular energy supply. In the past 12 years more than 50 point mutations and around 100 rearrangements in the mtDNA have been associated with human diseases. Also in recent years, several mutations in nuclear genes that encode structural or regulatory factors of the OXPHOS system or the mtDNA metabolism have been described. The development of increasingly powerful techniques and the use of cellular and animal models are opening new avenues in the study of mitochondrial medicine. The detailed molecular characterization of the effects produced by different mutations that cause mitochondrial cytopathies will be critical for designing rational therapeutic strategies for this group of devastating diseases.