Detection of Low Levels of the Mitochondrial tRNALeu(UUR) 3243A&gt;G Mutation in Blood Derived from Patients with Diabetes

Procaccio, Vincent; Neckelmann, Nicolas; Paquis‐Flucklinger, Véronique; Bannwarth, Sylvie; Jimenez, Richard; Dávila, Antonio; Poole, Jason C.; Wallace, Douglas C.

doi:10.1007/bf03256215

Cited by 10 publications

(15 citation statements)

References 28 publications

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“…A female carrying a pathogenic mtDNA mutation is at risk of passing the mutation to her offspring, even if she is asymptomatic with low-level heteroplasmy in somatic cells. In addition, there is growing evidence that somatic mtDNA alterations are associated with aging and a variety of common diseases, including diabetes and cancers (5)(6)(7)(8)(9)(10).…”

confidence: 99%

Comprehensive One-Step Molecular Analyses of Mitochondrial Genome by Massively Parallel Sequencing

2012

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BACKGROUND:Mitochondrial diseases are clinically and genetically heterogeneous, with variable penetrance, expressivity, and differing age of onset. Diseasecausing point mutations and large deletions in the mitochondrial genome often exist in a heteroplasmic state. Current molecular analyses require multiple different and complementary methods for the detection and quantification of mitochondrial DNA (mtDNA) mutations. We developed a novel approach to analyze the mtDNA in 1 step.

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confidence: 99%

Comprehensive One-Step Molecular Analyses of Mitochondrial Genome by Massively Parallel Sequencing

2012

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“…In fact, it now appears that about 1% of all Type II diabetes, a classic heterogeneous complex polygenic disease like autism, is due to this one mtDNA mutation, making it by far the most common known cause of diabetes mellitus. Many other mtDNA mutations that affect mitochondrial protein synthesis can also be expressed as type II diabetes and it is known that a patient is four times more likely to inherit type II diabetes from his mother than his father, consistent with mtDNA's pattern of inheritance [18] . Finally, mild mtDNA mutations have been associated with late-onset diseases [16] .…”

Section: Introductionmentioning

confidence: 93%

“…At a high percentage mutant (75-95%), this mutation can cause mitochondrial myopathy, stroke-like episodes and/or cardiac conduction defects and cardiomyopathy. However, at low levels of mutant (10-30%), this same mutation causes what appears to be a very different disease, Type II diabetes [18] . In fact, it now appears that about 1% of all Type II diabetes, a classic heterogeneous complex polygenic disease like autism, is due to this one mtDNA mutation, making it by far the most common known cause of diabetes mellitus.…”

Section: Introductionmentioning

confidence: 99%

“…Because of the fact that each tissue is derived from a progenitor cell that inherited a different mix of mitochondria from the fertilized egg there is no ideal single tissue in which to carry out a functional evaluation of mitochondria. Clearly rapidly proliferating cells pose the greatest challenge and while technology may soon make it useful [18] , currently it is rarely productive to use routine tests to identify mtDNA mutations in peripheral blood samples. Skin fibroblasts are far better than blood, but skeletal muscle is often selected as the best source, since this post-mitotic tissue hasn't suffered attrition of the most effected cells, those in which the defect will be easiest to observe.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Energy-Deficient Endophenotype in Autism

Gargus¹,

Imtiaz²,

Arabia³

2008

American J. of Biochemistry and Biotechnology

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Abstract:While evidence points to a multigenic etiology of most autism, the pathophysiology of the disorder has yet to be defined and the underlying genes and biochemical pathways they subserve remain unknown. Autism is considered to be influenced by a combination of various genetic, environmental and immunological factors; more recently, evidence has suggested that increased vulnerability to oxidative stress may be involved in the etiology of this multifactorial disorder. Furthermore, recent studies have pointed to a subset of autism associated with the biochemical endophenotype of mitochondrial energy deficiency, identified as a subtle impairment in fat and carbohydrate oxidation. This phenotype is similar, but more subtle than those seen in classic mitochondrial defects. In some cases the beginnings of the genetic underpinnings of these mitochondrial defects are emerging, such as mild mitochondrial dysfunction and secondary carnitine deficiency observed in the subset of autistic patients with an inverted duplication of chromosome 15q11-q13. In addition, rare cases of familial autism associated with sudden infant death syndrome (SIDS) or associated with abnormalities in cellular calcium homeostasis, such as malignant hyperthermia or cardiac arrhythmia, are beginning to emerge. Such special cases suggest that the pathophysiology of autism may comprise pathways that are directly or indirectly involved in mitochondrial energy production and to further probe this connection three new avenues seem worthy of exploration: 1) metabolomic clinical studies provoking controlled aerobic exercise stress to expand the biochemical phenotype, 2) high-throughput expression arrays to directly survey activity of the genes underlying these biochemical pathways and 3) model systems, either based upon neuronal stem cells or model genetic organisms, to discover novel genetic and environmental inputs into these pathways.

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“…These include high pressure liquid chromatography (dHPLC) of heteroduplexes (van den Bosch et al, 2000), restriction analysis resolved by dHPLC (Procaccio et al, 2006), luminex genotyping (Fuku et al, 2007), Surveyor nuclease-mediated heteroduplex digestion (Bannwarth et al, 2005), etc. Unfortunately, these methods can be limited by low throughput, high cost, inability to quantify heteroplasmy, or complexity in interpreting the results.…”

Section: Introductionmentioning

confidence: 99%

Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants

Poole¹,

Procaccio²,

Brandon³

et al. 2010

Biological Chemistry

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The mitochondrial DNA (mtDNA) encompasses two classes of functionally important sequence variants: recent pathogenic mutations and ancient adaptive polymorphisms. To rapidly and cheaply evaluate both classes of single nucleotide variants (SNVs), we have developed an integrated system in which mtDNA SNVs are analyzed by multiplex primer extension using the SNaPshot system. A multiplex PCR amplification strategy was used to amplify the entire mtDNA, a computer program identifies optimal extension primers, and a complete global haplotyping system is also proposed. This system genotypes SNVs on multiplexed mtDNA PCR products or directly from enriched mtDNA samples and can quantify heteroplasmic variants down to 0.8% using a standard curve. With this system, we have developed assays for testing the common pathogenic mutations in four multiplex panels: two genotype the 13 most common pathogenic mtDNA mutations and two genotype the 10 most common Leber Hereditary Optic Neuropathy mutations along with haplogroups J and T. We use a hierarchal system of 140 SNVs to delineate the major global mtDNA haplogroups based on a global phylogenetic tree of coding region polymorphisms. This system should permit rapid and inexpensive genotyping of pathogenic and lineage-specific mtDNA SNVs by clinical and research laboratories.

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Detection of Low Levels of the Mitochondrial tRNALeu(UUR) 3243A>G Mutation in Blood Derived from Patients with Diabetes

Cited by 10 publications

References 28 publications

Comprehensive One-Step Molecular Analyses of Mitochondrial Genome by Massively Parallel Sequencing

Comprehensive One-Step Molecular Analyses of Mitochondrial Genome by Massively Parallel Sequencing

Mitochondrial Energy-Deficient Endophenotype in Autism

Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants

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