A Case of a De Novo A3243G Mutation in Mitochondrial DNA in a Patient with Diabetes and Deafness

Maassen, J. A.; Biberoğlu, Sevinç; Hart, Leen M ’t; Bakker, E; Knijff, Peter de

doi:10.1076/apab.110.3.186.8294

Cited by 17 publications

(7 citation statements)

References 6 publications

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“…Under the assumption that mutation levels .50% may exist and have not been detected due to the small sample size, or that mutation levels in cells might increase in the first cell divisions, we predict that 1% of the oocytes will have a mutation level reaching above the threshold of expression. Combined with the calculated number of pathogenic mutations in oocytes, this would account for about 1:10 000 de novo cases of mtDNA disease, which is in line with the observed prevalence of OXPHOs disease and the high frequency of de novo mutations Thorburn, 2004) and which is supported by case reports on de novo mutations in severely affected patients (De Coo et al, 1996;Degoul et al, 1997;Maassen et al, 2002;Thorburn, 2004). In our study, no deletions were detected after analysis of the first round PCR products, but we only systematically analysed the shortest fragment, as the other two fragments were not visible on agarose gel.…”

Section: Discussionsupporting

confidence: 68%

mtDNA point mutations are present at various levels of heteroplasmy in human oocytes

Jacobs

Gerards²,

Chinnery

et al. 2007

MHR: Basic Science of Reproductive Medicine

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Little is known about the load of mutations and polymorphisms in the mitochondrial DNA (mtDNA) of human oocytes and the possible effect these mutations may have during life. To investigate this, we optimised at the single cell level the recently developed method to screen the entire mtDNA for mainly heteroplasmic mutations by denaturing high performance liquid chromatography analysis. This method is sensitive (approximately 1% heteroplasmy detectable), specific and rapid. The entire mtDNA of 26 oocytes of 13 women was screened by this method. Ten different heteroplasmic mutations, of which only one was located in the D-loop and two were observed twice, were detected in seven oocytes with mutation loads ranging from <5% to 50%. From eight women >1 oocyte was received and in four of them heteroplasmic differences between oocytes of the same woman were observed. In one of these four, two homoplasmic D-loop variants were also detected. Additionally, four oocytes of a single woman were sequenced using the MitoChip (which lacks the D-loop region), but all sequences were identical. It is concluded that heteroplasmic mtDNA mutations are common in oocytes and that, depending on the position and mutation load, they might increase the risk of developing OXPHOS disease early or later in life.

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Section: Discussionsupporting

confidence: 68%

mtDNA point mutations are present at various levels of heteroplasmy in human oocytes

Jacobs

Gerards²,

Chinnery

et al. 2007

MHR: Basic Science of Reproductive Medicine

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“…A mitochondrial haplotype analysis among Finnish individuals suggests that the A3243G mutation has occurred several times since the entry of Finnish tribes in Finland and that the number of carriers has expanded (13). Furthermore, a case of a de novo A3243G mutation in a Turkish pedigree has recently been identified by us (14). These observations suggest that the A3243G mutation is continuously generated in the human gene pool.…”

Section: Clinical Presentation Of Mitochondrial Diabetesmentioning

confidence: 83%

Mitochondrial Diabetes

et al. 2004

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Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic ␤-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in firstand second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic ␤-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed. Diabetes 53 (Suppl. 1):S103-S109, 2004 D iabetes is a collection of diseases characterized by the presence of chronic hyperglycemia. Maintenance of normal glucose homeostasis involves the action of a glucose sensor in the pancreatic ␤-cell that detects an increase in blood glucose concentration and converts that into increased secretion of insulin. Increased circulating insulin concentrations suppress hepatic glucose output and stimulate glucose uptake by muscle and adipose tissue.Pathophysiological mechanisms leading to diabetes can involve an inappropriate secretion of insulin, insulin resistance of the liver, muscle and fat, or combined defects. The risk of an individual to develop diabetes involves a complex interaction between genetic and environmental factors. Gene variants that have been identified to contribute to the major forms of diabetes, such as autoimmune type 1 diabetes and metabolic syndrome-associated type 2 diabetes, are "low penetrance" variants that modulate the susceptibility of an individual to develop diabetes or that protect against the disease (1-3).A number of gene mutants have been identified in the past decade that represent high penetrance risk genes for diabetes. Carriers of these gene mutants have a nearly 100% chance to develop diabetes during their life span. These so-called monogenetic forms of diabetes com...

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“…Among them, patients with type 2 DM like-characteristics can initially be treated with dietetic changes or sulfonylurea. Metformin is avoided because of the risk of exacerbating lactic acidosis (31). Patients with insulin-dependent diabetes require insulin from the time of diagnosis, and those with initial non-insulin dependent diabetes often progress rapidly to insulin therapy.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial diabetes and mitochondrial DNA mutation load in MELAS syndrome

Chae

Kim

et al. 2020

European Journal of Endocrinology

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Objective: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a very rare condition; it encompasses a diverse group of disorders including diabetes. Phenotypic variability can be attributed to heteroplasmy along with varying proportions of mutant and WT mitochondrial DNA (mtDNA). To examine the clinical relationship between mitochondrial diabetes and mutational load, we analyzed the mtDNA of children and young adolescents with MELAS syndrome using next generation sequencing (NGS). Design and methods: Of 57 subjects with suspected MELAS syndrome, 32 children and young adolescents were diagnosed as MELAS syndrome with mtDNA A-to-G transition at nucleotide 3243. Mutation load studies and NGS were performed for 25 subjects. Results: The mean mutation load was 60.4 ± 18.4% (range: 22.5‒100). Of the 25 subjects with NGS results, 15 (60%) were diagnosed with DM and 2 (8%) were diagnosed with impaired glucose tolerance (IGT). The mutational load of subjects inversely correlated with first symptom onset, age at diagnosis of MELAS syndrome, and DM (P < 0.001). However, mutational load did not correlate with the clinical severity or progression of DM/IGT. There was no significant difference in insulin resistance or sensitivity indices between the low- and high-mutation load groups. During the 3.7 years of follow-up, insulin resistance indices were not significantly different between baseline and follow-up. Conclusions: We can infer that the mutation load in the MELAS syndrome is significantly associated with the onset of symptoms and associated diseases, including mitochondrial diabetes. However, it may not influence disease progression.

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A Case of a De Novo A3243G Mutation in Mitochondrial DNA in a Patient with Diabetes and Deafness

Cited by 17 publications

References 6 publications

mtDNA point mutations are present at various levels of heteroplasmy in human oocytes

mtDNA point mutations are present at various levels of heteroplasmy in human oocytes

Mitochondrial Diabetes

Mitochondrial diabetes and mitochondrial DNA mutation load in MELAS syndrome

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