Mitochondrial DNA variant m.15218A &gt; G in Finnish epilepsy patients who have maternal relatives with epilepsy, sensorineural hearing impairment or diabetes mellitus

Soini, Heidi K.; Moilanen, Jukka S.; Vilmi-Kerälä, Tiina; Finnilä, Saara; Majamaa, Kari

doi:10.1186/1471-2350-14-73

Cited by 8 publications

(4 citation statements)

References 56 publications

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“…It indicated that the function of complex I may be associated with IR. Five of the above seven mtDNA variants were found in complex I in our study, which were previously reported in patients with diabetes ( 34 , 38 , 40 , 78 ). It may be due to the influence on the structure and the function of complex I, leading to IR and defecting the function of islets; thereby, these were considered to be possibly diabetes and DKD associated.…”

Section: Discussionsupporting

confidence: 84%

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Contribution of mitochondrial gene variants in diabetes and diabetic kidney disease

Gong

Han

et al. 2022

Front. Endocrinol.

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ObjectivesMitochondrial DNA (mtDNA) plays an important role in the pathogenesis of diabetes. Variants in mtDNA have been reported in diabetes, but studies on the whole mtDNA variants were limited. Our study aims to explore the association of whole mtDNA variants with diabetes and diabetic kidney disease (DKD).MethodsThe whole mitochondrial genome was screened by next-generation sequencing in cohort 1 consisting of 50 early-onset diabetes (EOD) patients with a maternally inherited diabetes (MID) family history. A total of 42 variants possibly associated with mitochondrial diseases were identified according to the filtering strategy. These variants were sequenced in cohort 2 consisting of 90 EOD patients with MID. The association between the clinical phenotype and these variants was analyzed. Then, these variants were genotyped in cohort 3 consisting of 1,571 type 2 diabetes mellitus patients and 496 subjects with normal glucose tolerance (NGT) to analyze the association between variants with diabetes and DKD.ResultsPatients with variants in the non-coding region had a higher percentage of obesity and levels of fasting insulin (62.1% vs. 24.6%, P = 0.001; 80.0% vs. 26.5% P < 0.001). The patients with the variants in rRNA had a higher prevalence of obesity (71.4% vs. 30.3%, P = 0.007), and the patients with the variants in mitochondrial complex I had a higher percentage of the upper tertile of FINS (64.3% vs. 34.3%, P = 0.049). Among 20 homogeneous variants successfully captured, two known variants (m.A3943G, m.A10005G) associated with other mitochondrial diseases were only in the diabetic group, but not in the NGT group, which perhaps indicated its possible association with diabetes. The prevalence of DKD was significantly higher in the group with the 20 variants than those without these variants (18.7% vs. 14.6%, P = 0.049) in the participants with diabetes of cohort 3.ConclusionMtDNA variants are associated with MID and DKD, and our findings advance our understanding of mtDNA in diabetes and DKD. It will have important implications for the individual therapy of mitochondrial diabetes.

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Section: Discussionsupporting

confidence: 84%

“…Another variant was the m.A15218G variant in MT-CYB. Previous research associated m.A15218G with epilepsy, diabetes, and Leber hereditary optic neuropathy (LHON) ( 78 , 80 ). This variant led to the substitution of a conserved hydrophilic threonine by a hydrophobic alanine at position 159 of the cytochrome b subunit of complex III.…”

Section: Discussionmentioning

confidence: 99%

Contribution of mitochondrial gene variants in diabetes and diabetic kidney disease

Gong

Han

et al. 2022

Front. Endocrinol.

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“…No variant predicted as deleterious by SIFT and probably damaging by PolyPhen was observed more than 3 times in the 436 samples sequenced, except the polymorphism rs2853506 (A15218G), which was observed in 10 samples (2%). This polymorphism has been found associated with epileptogenesis[ 30 ]. This SNP is located in the gene coding for cytochrome b, MT-CYB .…”

Section: Discussionmentioning

confidence: 99%

Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2

et al. 2015

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Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.

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“…Notably, polymorphisms that increase the risk of developing two or more diseases were limited to mitochondrial cytochrome b (CYB: H16R, T158A) and subunit 3 of cytochrome c oxidase (COIII: V91L, N154S) genes. The CYB variants H16R and T158A were previously associated with several diseases (31,32). The only non-synonymous polymorphism associated with a reduced risk of various entities was the G10398A (T114A) of ND3, which occurs twice on the human mtDNA phylogeny and has previously been associated with Parkinson's disease and cardiomyopathies (33)(34)(35)(36).…”

Section: Mitochondrial Dna Variants In Human Diseasesmentioning

confidence: 99%

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

et al. 2018

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High lactate production in cells during growth under oxygen-rich conditions (aerobic glycolysis) is a hallmark of tumor cells, indicating the role of mitochondrial function in tumorigenesis. In fact, enhanced mitochondrial biogenesis and impaired quality control are frequently observed in cancer cells. Mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS), is present in thousands of copies per cell, and has a very high mutation rate. Mutations in mtDNA and nuclear DNA (nDNA) genes encoding proteins that are important players in mitochondrial biogenesis and function are involved in oncogenic processes. A wide range of germline mtDNA polymorphisms, as well as tumor mtDNA somatic mutations have been identified in diverse cancer types. Approximately 72% of supposed tumor-specific somatic mtDNA mutations reported, have also been found as polymorphisms in the general population. The ATPase 6 and NADH dehydrogenase subunit genes of mtDNA are the most commonly mutated genes in breast cancer (BC). Furthermore, nuclear genes playing a role in mitochondrial biogenesis and function, such as peroxisome proliferators-activated receptor gamma coactivator-1 (PGC-1), fumarate hydratase (FH) and succinate dehydrogenase (SDH) are frequently mutated in cancer. In this review, we provide an overview of the mitochondrial germline variants and mutations in cancer, with particular focus on those found in BC.

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Mitochondrial DNA variant m.15218A > G in Finnish epilepsy patients who have maternal relatives with epilepsy, sensorineural hearing impairment or diabetes mellitus

Cited by 8 publications

References 56 publications

Contribution of mitochondrial gene variants in diabetes and diabetic kidney disease

Contribution of mitochondrial gene variants in diabetes and diabetic kidney disease

Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

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