Copyright © 1999 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 64, Issue 5, 1330-1339, 1 May 1999
doi:10.1086/302361
An mtDNA Mutation in the Initiation Codon of the Cytochrome C Oxidase Subunit II Gene Results in Lower Levels of the Protein and a Mitochondrial Encephalomyopathy
Kim M. Clark1, Robert W. Taylor1, Margaret A. Johnson1, Patrick F. Chinnery1, Zofia M.A. Chrzanowska-Lightowlers1, Richard M. Andrews2, Isobel P. Nelson3, Nicholas W. Wood3, Phillipa J. Lamont3, Michael G. Hanna3, Robert N. Lightowlers1 and Douglass M. Turnbull1, 
, 
1 Department of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, London
2 Department of Ophthalmology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, London
3 Neurogenetics Section, Department of Clinical Neurology, University of London, London
Address for correspondence and reprints: Prof. D. M. Turnbull, Department of Neurology, The Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom NE2 4HHAbstract
A novel heteroplasmic 7587T→C mutation in the mitochondrial genome which changes the initiation codon of the gene encoding cytochrome c oxidase subunit II (COX II), was found in a family with mitochondrial disease. This T→C transition is predicted to change the initiating methionine to threonine. The mutation load was present at 67% in muscle from the index case and at 91% in muscle from the patient's clinically affected son. Muscle biopsy samples revealed isolated COX deficiency and mitochondrial proliferation. Single-muscle-fiber analysis revealed that the 7587C copy was at much higher load in COX-negative fibers than in COX-positive fibers. After microphotometric enzyme analysis, the mutation was shown to cause a decrease in COX activity when the mutant load was >55%–65%. In fibroblasts from one family member, which contained >95% mutated mtDNA, there was no detectable synthesis or any steady-state level of COX II. This new mutation constitutes a new mechanism by which mtDNA mutations can cause disease-defective initiation of translation.
Article Information
PubMed
Related Articles
- Mitochondrial Encephalomyopathy and Complex III Deficiency A...Mitochondrial Encephalomyopathy and Complex III Deficiency Associated with a Stop-Codon Mutation in the Cytochrome b Gene
The American Journal of Human Genetics, Volume 67, Issue 6, 1 December 2000, Pages 1400-1410
J. Andrew Keightley, Roberto Anitori, Miriam D. Burton, Franklin Quan, Neil R.M. Buist and Nancy G. Kennaway
AbstractWe have reinvestigated a young woman, originally reported by us in 1983, who presented with exercise intolerance and lactic acidosis associated with severe deficiency of complex III and who responded to therapy with menadione and ascorbate. Gradually, she developed symptoms of a mitochondrial encephalomyopathy. Immunocytochemistry of serial sections of muscle showed a mosaic of fibers that reacted poorly with antibodies to subunits of complex III but reacted normally with antibodies to subunits of complexes I, II, or IV, suggesting a mutation of mtDNA. These findings demonstrate the diagnostic value of immunocytochemistry in identifying specific respiratory-chain deficiencies and, potentially, distinguishing between nuclear- or mtDNA-encoded defects. Sequence analysis revealed a stop-codon mutation (G15242A) in the mtDNA-encoded cytochrome b gene, resulting in loss of the last 215 amino acids of cytochrome b. PCR-RFLP analysis indicated that the G15242A mutation was heteroplasmic and was present in a high percentage (87%) of affected tissue (skeletal muscle) and a low percentage (0.7%) of unaffected tissue (blood) but was not detected in controls. Analysis of microdissected muscle fibers showed a significant correlation between the immunoreactivity toward the Rieske protein of complex III and the percentage of mutant mtDNA: immunopositive fibers had a median value of 33% of the G15242A mutation, whereas immunonegative, ragged-red fibers had a median value of 89%, indicating that the stop-codon mutation was pathogenic in this patient. The G15242A mutation was also present in several other tissues, including hair roots, indicating that it must have arisen either very early in embryogenesis, before separation of the primary germ layers, or in the maternal germ line. The findings in this patient are contrasted with other recently described patients who have mutations in the cytochrome b gene.
Abstract | | - The Myoclonic Epilepsy and Ragged-Red Fiber Mutation Provide...The Myoclonic Epilepsy and Ragged-Red Fiber Mutation Provides New Insights into Human Mitochondrial Function and Genetics
The American Journal of Human Genetics, Volume 62, Issue 4, 1 April 1998, Pages 745-751
Anne Chomyn
| - Selection against Pathogenic mtDNA Mutations in a Stem Cell ...Selection against Pathogenic mtDNA Mutations in a Stem Cell Population Leads to the Loss of the 3243A→G Mutation in Blood
The American Journal of Human Genetics, Volume 82, Issue 2, 8 February 2008, Pages 333-343
Harsha Karur Rajasimha, Patrick F. Chinnery and David C. Samuels
AbstractThe mutation 3243A→G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mution decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.
Abstract | | - …more
