Nuclear genes and mitochondrial translation: a new class of genetic disease
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Nuclear gene
Mitochondrial disease
Human mitochondrial genetics
Nuclear DNA
MT-RNR1
Pseudogene
Nuclear DNA
Nuclear gene
Heteroplasmy
Human mitochondrial genetics
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Abstract Background The diagnosis of mitochondrial disorders is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next‐Generation Sequencing (NGS) technology offers a robust high‐throughput platform for nuclear and mitochondrial DNA (mtDNA) analyses. Method We developed a custom Agilent SureSelect Mito chondrial a nd N uclear D isease Panel (Mito‐aND‐Panel) capture kit that allows parallel enrichment for subsequent NGS‐based sequence analysis of nuclear mitochondrial disease‐related genes and the complete mtDNA genome. Sequencing of enriched mtDNA simultaneously with nuclear genes was compared with the separated sequencing of the mitochondrial genome and whole exome sequencing (WES). Results The Mito‐aND‐Panel permits accurate detection of low‐level mtDNA heteroplasmy due to a very high sequencing depth compared to standard diagnostic procedures using Sanger sequencing/SNaPshot and WES which is crucial to identify maternally inherited mitochondrial disorders. Conclusion We established a NGS‐based method with combined sequencing of the complete mtDNA and nuclear genes which enables a more sensitive heteroplasmy detection of mtDNA mutations compared to traditional methods. Because the method promotes the analysis of mtDNA variants in large cohorts, it is cost‐effective and simple to setup, we anticipate this is a highly relevant method for sequence‐based genetic diagnosis in clinical diagnostic applications.
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Nuclear gene
Mitochondrial disease
Human mitochondrial genetics
Nuclear DNA
MT-RNR1
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Mitochondrial disorders are clinical phenotypes associated with mitochondrial dysfunction, which can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear genes. In this review, we summarized the pathogenic mutations of nuclear genes associated with mitochondrial disorders. These nuclear genes encode, components of mitochondrial translational machinery and structural subunits and assembly factors of the oxidative phosphorylation, that complex. The molecular mechanisms, that nuclear modifier genes modulate the phenotypic expression of mtDNA mutations, are discussed in detail.
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Mitochondrial disorders have become the most common cause of inborn errors of metabolism. Impairments in mitochondrial protein synthesis are one of the causes of these diseases, which are clinically and genetically heterogeneous. The mitochondrial translation machinery decodes 13 polypeptides essential for the oxidative phosphorylation process. Mitochondria protein synthesis depends on the integrity of mitochondrial rRNAs and tRNAs genes, and at least one hundred of nuclear encoded products. Diseases caused by mutations in mitochondrial genes as well as in ribosomal proteins, translational factors, RNA modifying enzymes, and all other constituents of the translational machinery have been described in patients with combine respiratory chain deficiency, and are the object of this review.
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Mitochondrial respiratory chain diseases are a highly diverse group of disorders whose main unifying characteristic is the impairment of mitochondrial function. As befits an organelle containing gene products encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), these diseases can be caused by inherited errors in either genome, but a surprising number are sporadic, and a few are even caused by environmental factors.
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The multiple functions of mitochondria, including adenosine triphosphate synthesis, are controlled by the coordination of both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) genomes. Mitochondrial disorders manifest because of impairment of energy metabolism. This article focuses on mutations in two nuclear genes and their effect on mitochondrial function. Mutations in the polymerase gamma, or POLG, gene are associated with multisystemic disease processes, including Alpers Syndrome, a severe childhood-onset syndrome. Mutations in the OPA1 gene are associated with autosomal dominant optic atrophy and other neurologic, musculoskeletal, and ophthalmologic symptoms. When assessing for disorders affecting energy metabolism, sequencing of both the mtDNA genome and the nDNA whole exome sequencing is necessary.
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Part I: Mitochondrial Disorder: A Complex Disease of the Two Genomes 1. Mitochondrial DNA Mutations: An Overview of Clinical and Molecular Aspects William J. Craigen 2. Nuclear Gene Defects in Mitochondrial Disorders Fernando Scaglia 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders 3. Diagnostic Challenges of Mitochondrial Disorders: Complexities of Two Genomes Brett H. Graham Part II: Biochemical Analysis of Mitochondrial Disorders 4. Biochemical Analyses of the Electron Transport Chain Complexes by Spectrophotometry 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Ann E. Frazier and David R. Thorburn 5. Measurement of Mitochondrial Oxygen Consumption Using A Clark Electrode Zhihong Li and Brett H. Graham 6. Mitochondrial Respiratory Chain: Biochemical Analysis and Criterion for Deficiency in Diagnosis 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Manuela M. Grazina 7. Assays of Pyruvate Dehydrogenase Complex and Pyruvate Carboxylase Activity 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Douglas Kerr, George Grahame, and Ghunwa Nakouzi 8. Assessment of Thymidine Phosphorylase Function: Measurement of Plasma Thymidine (and Deoxyuridine) and Thymidine Phosphosphorylase Activity 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Ramon Marti, Luis C. Lopez, and Michio Hirano 9. Measurement of Mitochondrial dNTP Pools 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Ramon Marti, Beatriz Dorado, and Michio Hirano 10. Measurement of Oxidized and Reduced Coenzyme Q in Biological Fluids, Cells, and Tissues: An HPLC-EC Method 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Peter H. Tang and Michael V. Miles 11. Assay to Measure Oxidized and Reduced Forms of CoQ by LC-MS/MS 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Si Houn Hahn, Sandra Kerfoot, and Valeria Vasta 12. Morphological Assessment of Mitochondrial Respiratory Chain Function on Tissue Sections 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Kurenai Tanji 13. Blue Native Polyacrylamide Gel Electrophoresis: A Powerful Diagnostic Tool for the Detection of Assembly Defects in the Enzyme Complexes of Oxidative Phosphorylation 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Scot C. Leary 14. Radioactive Labeling of Mitochondrial Translation Products in Cultured Cells 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Florin Sasarman and Eric A. Shoubridge 15. Transmitochondrial Cybrids: Tools for Functional Studies of Mutant Mitochondria 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Sajna Antony Vithayathil, Yewei Ma, and Benny Abraham Kaipparettu 16. Fluorescence-Activated Cell Sorting Analysis of Mitochondrial Content, Membrane Potential, and Matrix Oxidant Burden in Human Lymphoblastoid Cell Lines 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Stephen Dingley, Kimberly A. Chapman, and Marni J. Falk 17. Molecular Profiling of Mitochondrial Dysfunction in Caenorhabditis elegans 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Erzsebet Polyak, Zhe Zhang, and Marni J. Falk Part III: Molecular Analysis of Mitochondrial Disorders 18. Analysis of Common Mitochondrial DNA Mutations by Allele-Specific Oligonucleotide and Southern Blot Hybridization 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Sha Tang, Michelle C. Halberg, Kristen C. Floyd, and Jing Wang Megan L. Landsverk, Megan E. Cornwell, and Meagan E. Palculict 20. Utility of Array CGH in Molecular Diagnosis of Mitochondrial Disorders Jing Wang and Mrudula Rakhade 21. Quantification of mtDNA Mutation Heteroplasmy (ARMS qPCR) Victor Venegas and Michelle C. Halberg 22. Measurement of Mitochondrial DNA Copy Number Victor Venegas and Michelle C. Halberg 23. Determination of the Clinical Significance of an Unclassified Variant Victor Wei Zhang and Jing Wang 19. Sequence Analysis of the Whole Mitochondrial Genome and Nuclear Genes Causing Mitochondrial Disorders Megan L. Landsverk, Megan E. Cornwell, and Meagan E. Palculict 20. Utility of Array CGH in Molecular Diagnosis of Mitochondrial Disorders Jing Wang and Mrudula Rakhade 21. Quantification of mtDNA Mutation Heteroplasmy (ARMS qPCR) Victor Venegas and Michelle C. Halberg 22. Measurement of Mitochondrial DNA Copy Number Victor Venegas and Michelle C. Halberg 23. Determination of the Clinical Significance of an Unclassified Variant Victor Wei Zhang and Jing Wang
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Purpose Mitochondrial abnormalities are major causes of human disease. Pearson syndrome illustrates many features of abnormal mitochondrial function and genetics. Design Mitochondria form adenosine triphosphate (ATP) via five multienzyme complexes of the electron transport chain and oxidative phosphorylation, composed from a blend of nuclear and mitochondrial gene products. Mitochondrial DNA (mtDNA) is small (16.6 kb), encoding some subunits of these complexes as well as transfer RNA (tRNA) and ribosomal RNA, but is replicated and transcribed by nuclear encoded polymerases. Multiple copies of mtDNA are passed on to progeny cells via the cytoplasm, accounting for maternal inheritance. Normal and mutant mtDNA can coexist within the same cell (heteroplasmy); when the proportion of mutant mtDNA exceeds a threshold, cellular function is impaired, resulting in disease. Results and Conclusions MtDNA abnormalities include point mutations, deletions, and depletion. Point mutations in an enzyme subunit cause a specific disorder, whereas point mutations in the tRNAs result in general impairment of protein synthesis and are associated with a variety of disorders. Large mtDNA deletions, initially described in Kearns-Sayre syndrome (KSS), were found soon thereafter in Pearson syndrome. Survivors of Pearson syndrome have gone on to develop KSS. A whole spectrum of disease forms, ranging from isolated sideroblastic anemia to combined Pearson and KSS, are associated with delections of mtDNA. Diagnosis of mitochondrial disorders depends on clinical suspicion, enhanced by evidence of abnormal mitochondrial structure, number, and/or function. Effective treatment for mitochondrial disorders is very limited, including correction of the metabolic milieu, activation of enzyme activity by drugs or cofactors, and removal of reactive oxygen species.
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Mitochondrial disease
Human mitochondrial genetics
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Mitochondrial disorders are caused by deficient respiratory chain function, resulting in a complex series of pathophysiological events. Genetic counselling is complicated because the respiratory chain subunits are encoded by both nuclear and mitochondrial DNA genes. Only a minority of the nuclear genes involved in mitochondrial function have been identified, and even fewer are associated with human mitochondrial disease. Mutations in mitochondrial DNA are particularly challenging because of the complexities of mitochondrial genetics: the mitochondrial DNA is strictly maternally inherited; there are 103–104 copies of mitochondrial DNA in somatic cells; affected individuals often have a mixture of normal and mutated mitochondrial DNA (mitochondrial DNA heteroplasmy), the level of mutated mitochondrial DNA (the mitochondrial DNA mutation load) may vary widely between different maternally related individuals, between tissues and with time; a particular minimal threshold of mutated mitochondrial DNA is required to impair respiratory chain function; and there is not always a good correlation between mutant load and phenotype.
Heteroplasmy
Human mitochondrial genetics
Mitochondrial disease
Nuclear DNA
DNAJA3
Mitochondrial respiratory chain
MT-RNR1
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