A homoplasmic mtDNA variant can influence the phenotype of the pathogenic m.7472Cins MTTS1 mutation: are two mutations better than one?
Open accessAbstract
Mutations in mitochondrial tRNA (mt-tRNA) genes are well recognized as a common cause of human disease, exhibiting a significant degree of clinical heterogeneity. While these differences are explicable, in part, by differences in the innate pathogenicity of the mutation, its distribution and abundance, other factors, including nuclear genetic background, mitochondrial DNA (mtDNA) haplotype and additional mtDNA mutations may influence the expression of mt-tRNA mutations. We describe the clinical, biochemical and molecular findings in a family with progressive myopathy, deafness and diabetes and striking respiratory chain abnormalities due to a well-characterized heteroplasmic mt-tRNA mutation in the mt-tRNA(Ser(UCN)) (MTTS1) gene. In addition to the m.7472Cins mutation, all individuals were homoplasmic for another variant, m.7472A > C, affecting the adjacent nucleotide in the mt-tRNA(Ser(UCN)) structure. In addition to available patient tissues, we have analysed transmitochondrial cybrid clones harbouring homoplasmic levels of m.7472A > C and varying levels of the m.7472Cins mutation in an attempt to clarify the precise role of the m.7472A > C transversion in the underlying respiratory chain abnormality. Evidence from both in vivo and in vitro studies demonstrate that the m.7472A > C is able to modify the expression of the m.7472Cins mutation and would suggest that it is not a neutral variant but appears to cause a biochemical defect by itself, confirming that homoplasmic mtDNA variants can modulate the phenotypic expression of pathogenic, heteroplasmic mtDNA mutations.
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Certain nucleotide changes that are not pathogenic per se may modulate the effects of deleterious mtDNA mutations.
“Also, it has been frequently recognised that certain nucleotide changes that are not pathogenic per se may modulate the effects of deleterious mtDNA mutations [84,85].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [84]
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Mitochondrial DNA mutations and human disease
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Self-citation
- Authors
- Swalwell, H., Blakely, E. L., Sutton, R., Tonska, K., Elstner, M., He, L., Taivassalo, T., Burns, D. K., Turnbull, D. M., Haller, R. G., Davidson, M. M., & Taylor, R. W.
- Affiliations
- Newcastle University (GB)
- Ludwig-Maximilians-Universität München (DE)
- McGill University (CA)
- The University of Texas Southwestern Medical Center (US)
- Texas Health Dallas (US)
- Columbia University (US)
- Corresponding author
- Taylor, Robert W
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2008-04-09
- Volume
- 16
- Issue
- 10
- Pages
- 1265-1274
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- OpenAlex
- W2070231746
- Cited by
- 34
- References
- 30
- Citations by year
- 2024: 2 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 7
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Muscular Dystrophy Association
- United Mitochondrial Disease Foundation
- Wellcome Trust (074454)
- Newcastle upon Tyne Hospitals NHS Foundation Trust
- Muscular Dystrophy UK
- 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 › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- mitochondrial disease, progressive myopathy, deafness, diabetes mellitus, phenotypic expression, mitochondrial haplotypes
- MeSH terms
- Aged, Base Sequence, Biological Assay, Clone Cells, Electron Transport Complex IV, DNA Mutational Analysis, DNA, Mitochondrial, Electron Transport, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Pedigree, Phenotype, RNA, Transfer, Succinate Dehydrogenase, Protein Biosynthesis, Blotting, Northern, Muscle, Skeletal, Mitochondrial Proteins
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