Techniques and Pitfalls in the Detection of Pathogenic Mitochondrial DNA Mutations

Moraes, Carlos T.; Atencio, David P.; Oca‐Cossio, Jose; Díaz, Francisca

doi:10.1016/s1525-1578(10)60474-6

Cited by 54 publications

(36 citation statements)

References 71 publications

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“…50). Because it is difficult to predict the effect any given nucleotide variant may have on the secondary and tertiary structure of a tRNA (27,74), it is therefore difficult to hypothesize that the variant causes an observed phenotype (49). However, with some knowledge of …”

Section: Rna Genes and The D-loopmentioning

confidence: 99%

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Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

Schlick

Jensen‐Seaman²,

Orlebeke³

et al. 2006

American Journal of Physiology-Cell Physiology

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quence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains. Am J Physiol Cell Physiol 291: C1183-C1192, 2006. First published July 19, 2006 doi:10.1152/ajpcell.00234.2006.-Rat remains a major biomedical model system for common, complex diseases. The rat continues to gain importance as a model system with the completion of its full genomic sequence. Although the genomic sequence has generated much interest, only three complete sequences of the rat mitochondria exist. Therefore, to increase the knowledge of the rat genome, the entire mitochondrial genomes (16,307-16,315 bp) from 10 inbred rat strains (that are standard laboratory models around the world) and 2 wild rat strains were sequenced. We observed a total of 195 polymorphisms, 32 of which created an amino acid change (nonsynonymous substitutions) in 12 of the 13 protein coding genes within the mitochondrial genome. There were 11 single nucleotide polymorphisms within the tRNA genes, six in the 12S rRNA, and 12 in the 16S rRNA including 3 insertions/deletions. We found 14 single nucleotide polymorphisms and 2 insertion/deletion polymorphisms in the D-loop. The inbred rat strains cluster phylogenetically into three distinct groups. The wild rat from Tokyo grouped closely with five inbred strains in the phylogeny, whereas the wild rat from Milwaukee was not closely related to any inbred strain. These data will enable investigators to rapidly assess the potential impact of the mitochondria in these rats on the physiology and the pathophysiology of phenotypes studied in these strains. Moreover, these data provide information that may be useful as new animal models, which result in novel combinations of nuclear and mitochondrial genomes, are developed. genome; mitochondria MITOCHONDRIA ARE THE ONLY organelles (other than the nucleus) with their own DNA, which is maternally inherited (31, 36). The mammalian mitochondrial DNA (mtDNA) is a circular, double-stranded DNA that lacks introns and has only ϳ7% noncoding sequences (23) in contrast to the genomic DNA. The mtDNA encodes 37 genes, including 13 protein-coding genes that, in conjunction with subunits encoded by the nuclear genome, form the electron transport chain, the primary ATP producer for the cell. Also included within these 37 coding genes are 22 tRNA genes whose function is to transport amino acids to the ribosome and match them to the codons of the mRNAs thus facilitating incorporation of amino acids into the growing polypeptide during translation. The final 2 genes are rRNA genes. The D-loop or control region, although noncoding, contains binding sites for two transcription factors, three conserved sequence blocks (CSBs) associated with initiation of replication and the loop strand termination associated sequences (9,21,23,61

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Section: Rna Genes and The D-loopmentioning

confidence: 99%

“…It is generally accepted that mtDNA mutations can be major contributors to human pathologies and possibly to aging. However, heteroplasmy (the mixture of wild-type and mutated mtDNA within a cell) can further complicate the detection and development of disease (49,66).…”

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confidence: 99%

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

Schlick

Jensen‐Seaman²,

Orlebeke³

et al. 2006

American Journal of Physiology-Cell Physiology

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show abstract

“…Molecular diagnostic techniques have greater inter-laboratory reproducibility [7]. However, mtDNA analysis presents a particular diagnostic challenge in that false negative results may result from low level heteroplasmy in peripheral blood samples [8]. Various molecular methodologies are under evaluation by different laboratories to overcome these diagnostic challenges.…”

Section: Introductionmentioning

confidence: 99%

The in-depth evaluation of suspected mitochondrial disease

Haas

Parikh

Falk

et al. 2008

Molecular Genetics and Metabolism

318

300

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Mitochondrial disease confirmation and establishment of a specific molecular diagnosis requires extensive clinical and laboratory evaluation. Dual genome origins of mitochondrial disease, multiorgan system manifestations, and an ever increasing spectrum of recognized phenotypes represent the main diagnostic challenges. To overcome these obstacles, compiling information from a variety of diagnostic laboratory modalities can often provide sufficient evidence to establish an etiology. These include blood and tissue histochemical and analyte measurements, neuroimaging, provocative testing, enzymatic assays of tissue samples and cultured cells, as well as DNA analysis. As interpretation of results from these multifaceted investigations can become quite complex, the Diagnostic Committee of the Mitochondrial Medicine Society developed this review to provide an overview of currently available and emerging methodologies for the diagnosis of primary mitochondrial disease, primarily focusing on disorders characterized by impairment of oxidative phosphorylation. The aim of this work is to facilitate the diagnosis of mitochondrial disease by geneticists, neurologists, and other metabolic specialists who face the challenge of evaluating patients of all ages with suspected mitochondrial disease.

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“…For variants in the mtDNA, however, this may be particularly challenging, given that the level of cellular heteroplasmy, together with the tissue distribution, can markedly influence clinical expression. 31,32 This could also, at least in part, explain the clinically unaffected status of the mother of the dizygotic twins (Patients 12 and 13) who were both affected with cardiomyopathy, albeit to different degrees. She shared a previously unreported homoplasmic change (5494TϾG) with both children (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA analysis by multiplex denaturing high-performance liquid chromatography and selective sequencing in pediatric patients with cardiomyopathy

Schrijver¹,

Pique

Traynis

et al. 2009

Genetics in Medicine

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Purpose: Mitochondrial DNA testing is typically performed by targeted mutation analysis only. We applied a more comprehensive approach to study the mitochondrial genome in 24 pediatric patients with idiopathic cardiomyopathy. Methods: Patients in the cohort did not show overt multisystemic disease and were previously tested for mutations in a subset of structural genes associated with cardiomyopathy. Mutation screening of the mitochondrial DNA by multiplex denaturing highperformance liquid chromatography was complemented by sequence analysis. Results: We identified 130 individual (unique) sequence changes. Among several potentially pathogenic changes, a novel heteroplasmic mutation in nicotinamide adenine dinucleotide dehydrogenase subunit 4 (10677GϾA) was identified in one fraternal twin with worse clinical symptoms than his sibling. Another proband carried homoplasmic mutation 13708GϾA (in nicotinamide adenine dinucleotide dehydrogenase subunit 5) that has been associated with Leber's hereditary optic neuropathy. Conclusions: Changes in mitochondrial DNA may represent a relatively rare cause of idiopathic pediatric cardiomyopathies and/or influence their phenotypic expression. Interpretation of variants with uncertain pathogenicity, however, currently impedes clinical diagnostic use of comprehensive mitochondrial DNA testing. Whereas combined use of multiplex denaturing high-performance liquid chromatography and sequencing is more comprehensive than targeted mutation analysis, measurement of additional functional parameters, such as tissue respiratory chain activity, remains important to establishing a definitive diagnosis. Genet Med 2009:11(2):118 -126.

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Techniques and Pitfalls in the Detection of Pathogenic Mitochondrial DNA Mutations

Cited by 54 publications

References 71 publications

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

The in-depth evaluation of suspected mitochondrial disease

Mitochondrial DNA analysis by multiplex denaturing high-performance liquid chromatography and selective sequencing in pediatric patients with cardiomyopathy

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