Age of onset possibly associated with the degree of heteroplasmy in two male siblings with diabetes mellitus having an A to G transition at 3243 of mitochondrial DNA

Kato, Yuzuru; Miura, Yoshitaka; Inagaki, Akemi; Itatsu, Takeharu; Oiso, Yutaka

doi:10.1046/j.1464-5491.2002.00777.x

Cited by 7 publications

(3 citation statements)

References 19 publications

(19 reference statements)

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“…The most common endocrine manifestation of MIDD is short stature [9,110–113], because of hypothalamic growth hormone‐releasing hormone deficiency [114]. Along with short stature, MIDD patients are frequently thin [body mass index (BMI) < 20.0 kg/m 2 ][54], particularly those that progress to insulin requirement early in their disease.…”

Section: Clinical Featuresmentioning

confidence: 99%

Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation

et al. 2008

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Maternally inherited diabetes and deafness (MIDD) affects up to 1% of patients with diabetes but is often unrecognized by physicians. It is important to make an accurate genetic diagnosis, as there are implications for clinical investigation, diagnosis, management and genetic counselling. This review summarizes the range of clinical phenotypes associated with MIDD; outlines the advances in genetic diagnosis and pathogenesis of MIDD; summarizes the published prevalence data and provides guidance on the clinical management of these patients and their families.

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Section: Clinical Featuresmentioning

confidence: 99%

Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation

et al. 2008

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“…We concentrated on the 3243A/G and 8344A/G mutations because of the relatively large amount of data available for these two mutations. A total of 275 unique data pairs were identified for 3243A/G, 3,4,[12][13][14][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] and 48 unique data pairs were identified for 8344A/G. [38][39][40][41][42] For the 3243A/G mutation, a subset of these studies was identified that also reported mtDNA heteroplasmy in muscle tissue.…”

Section: Clinical Datamentioning

confidence: 99%

Selection against Pathogenic mtDNA Mutations in a Stem Cell Population Leads to the Loss of the 3243A→G Mutation in Blood

Rajasimha

Chinnery

Samuels

2008

The American Journal of Human Genetics

106

103

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The mutation 3243A-->G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mutation decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.

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“…Once this is exceeded, large changes in the phenotype can be observed with minor increases in the proportion of the mutant mtDNA. Another mutation, A3243A/G, may be related to age of onset of diabetes mellitus depending on the degree of mtDNA heteroplasmy (Guttman et al, 2001; Kato et al, 2002)and levels of mtDNA 3243A/G heteroplasmy are higher in diabetics than non-diabetics(Coon et al, 2006) (Majamaa-Voltti et al, 2006). Additional heteroplasmic mutations related to diabetes, hyperglycemia, insulin dependence and obesity include 3398T/C (Chen et al, 2000), 3254C/A (Chen et al, 2000), 3316G/A (Chen et al, 2000), 3156A/G (Ohkubo et al, 2001), 3357G/A (Ohkubo et al, 2001), 3375C/A (Ohkubo et al, 2001), and 3394T/C (Chen et al, 2000; Ohkubo et al, 2001).…”

Section: Mitochondrial Dna Somatic Mutationsmentioning

confidence: 99%

Mitochondrial–nuclear epistasis: Implications for human aging and longevity

Tranah

2011

Ageing Research Reviews

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There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genomes. Results from Drosophila suggest that the effects of mtDNA haplotypes on longevity vary among different nuclear allelic backgrounds, which could account for the inconsistent associations that have been observed between mitochondrial DNA (mtDNA) haplogroups and survival in humans. A diversity of pathways may influence the way mitochondria and nuclear – mitochondrial interactions modulate longevity, including: oxidative phosphorylation; mitochondrial uncoupling; antioxidant defenses; mitochondrial fission and fusion; and sirtuin regulation of mitochondrial genes. We hypothesize that aging and longevity, as complex traits having a significant genetic component, are likely to be controlled by nuclear gene variants interacting with both inherited and somatic mtDNA variability.

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Age of onset possibly associated with the degree of heteroplasmy in two male siblings with diabetes mellitus having an A to G transition at 3243 of mitochondrial DNA

Cited by 7 publications

References 19 publications

Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation

Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation

Selection against Pathogenic mtDNA Mutations in a Stem Cell Population Leads to the Loss of the 3243A→G Mutation in Blood

Mitochondrial–nuclear epistasis: Implications for human aging and longevity

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