A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes.
Abstract
From a family of 16 diabetic patients with typical maternal inheritance, we investigated a 69-year-old woman with type 2 diabetes. The proband showed no major deletions in the mitochondrial DNA (mtDNA). Direct sequencing revealed 7 missense and 5 ribosomal RNA homoplasmic nucleotide substitutions when compared with the Cambridge Sequence and its recent revision. When compared with the control cybrid cells, the proband cybrid cells showed 6 nucleotide substitutions. Among these, 14577 T/C, which turned out to be 98.9% heteroplasmic, is a new missense substitution in the NADH dehydrogenase 6 gene. We also observed 2 other patients with 14577 T/C substitution from another group of 252 unrelated diabetic patients, whereas no individual from a group of 529 control subjects had 14577 T/C substitution. Furthermore, these 6 substitutions were in linkage disequilibrium. Mitochondrial respiratory chain complex I activity and O2 consumption rates of the proband cybrid cells, which were obtained by the fusion of mtDNA-deleted (rho0) HeLa cells and mtDNA from the proband, showed 64.5 and 61.5% reductions, respectively, compared with control cybrid cells. The present study strongly indicates that the new mtDNA mutation at 14577 T/C is probably a major pathogenic mutation for type 2 diabetes in this family.
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Mutation 14577 T>C, a missense substitution in the NADH dehydrogenase 6 gene, is another example of an mtDNA mutation associated with diabetes.
“Another example is mutation 14577 TϾC, a missense substitution in the NADH dehydrogenase 6 gene (245).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [245]
In hybrid cell lines derived from probands with the 14577 T>C mutation, mitochondrial respiratory chain complex I activity and O2 consumption rates are decreased by 65 and 62%, respectively.
“In this case, mitochondrial respiratory chain complex I activity and O 2 consumption rates are decreased by 65 and 62%, respectively, in hybrid cell lines derived from probands.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [245]
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- Authors
- Tawata, M., Hayashi, J. I., Isobe, K., Ohkubo, E., Ohtaka, M., Chen, J., Aida, K., & Onaya, T.
- Affiliations
- Third Department of Internal Medicine, Yamanashi Medical University, Tamaho, Japan. tawatam@res.yamanashi-med.ac.jp
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2000-07-01
- Volume
- 49
- Issue
- 7
- Pages
- 1269-1272
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2114101869
- Cited by
- 69
- References
- 20
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 1 · 2014: 1 · 2013: 2 · 2012: 3
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- mitochondrial DNA mutations, type 2 diabetes, ND6, missense substitutions, cybrid cells, oxygen consumption, linkage disequilibrium, pathogenic variants
- MeSH terms
- Aged, Cytochrome b Group, Diabetes Mellitus, Type 2, DNA, Mitochondrial, Female, HeLa Cells, Humans, Hybrid Cells, Male, Mitochondria, NADH Dehydrogenase, Oxygen Consumption, Pedigree, RNA, Ribosomal, RNA, Ribosomal, 16S, Genomic Imprinting, Mutation, Missense
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