The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Construction of Transgenic Mice with Tissue-Specific Acceleration of Mitochondrial DNA Mutagenesis
Abstract
Transgenic mice having rapid accumulation of mitochondrial DNA (mtDNA) mutations specifically in the heart were created. These mice contained a transgene encoding a proofreading-deficient, mouse mitochondrial DNA polymerase (pol gamma) driven by the promoter for the cardiac-specific alpha-myosin heavy chain. Starting shortly after birth greater than 95% of all pol gamma mRNA in the heart was transgene derived; expression in other tissues was low or absent. Mutations in cardiac mtDNA began to accumulate by 7 days after birth. At 1 month of age the frequency of point mutations was 0.014% as determined by DNA sequencing of cloned mtDNA. By long-extension PCR multiple different deletion mutations that had removed several thousand basepairs of genomic sequence were also detected. Sequencing of two deletion molecules showed that one was flanked at the breakpoint by direct repeat sequences. The expression of proofreading-deficient pol gamma had no apparent deleterious effect on mitochondrial DNA and protein content, gene expression, or respiratory function. However, associated with the rise in mtDNA mutation levels was the development of cardiomyopathy as evidenced by enlarged hearts in the transgenic mice. These mice may prove to be useful models to study the pathogenic effects of elevated levels of mitochondrial DNA mutations in specific tissues.
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“In mice, transgenic overexpression of exonuclease-deficient Pol γ in cardiac tissue caused a greater than 23-fold increase in mtDNA point mutations and detectable levels of large mtDNA deletions (Zhang et al., 2000).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Zhang et al., 2000
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Metadata
- Authors
- Zhang, D., Mott, J. L., Chang, S.-W., Denniger, G., Feng, Z., & Zassenhaus, H. P.
- Affiliations
- Saint Louis University (US)
- Corresponding author
- Zassenhaus, Hans Peter
- Venue
- Genomics
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 69
- Issue
- 2
- Pages
- 151-161
- ISSN
- 0888-7543 (ISSN-L)
- OpenAlex
- W2005953994
- Semantic Scholar
- 06cd373df65f3ec58a4f2624719fa0f5a724bec7
- Cited by
- 124
- References
- 44
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 6 · 2015: 6 · 2014: 4 · 2013: 6 · 2012: 3
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Genomics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- transgenic mice, alpha-myosin heavy chain promoter, cardiomyopathy, mitochondrial DNA deletions, direct repeats, tissue-specific mutagenesis, heart
- MeSH terms
- DNA Polymerase gamma, Animals, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Genes, Dominant, Heart, Mice, Transgenic, Mitochondria, Heart, Mutation, Organ Specificity, Mutagenesis, Gene Expression Profiling, Mice
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