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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants

Jason C. Poole1, 2 / Vincent Procaccio1, 3, 4 / Martin C. Brandon1 / Greg Merrick1 / Douglas C. Wallace1, 5

1Center for Molecular and Mitochondrial Medicine and Genetics, Departments of Ecology and Evolutionary Biology, Biological Chemistry, and Pediatrics, University of California, Irvine, CA 92697, USA

2Department of Molecular Biology, EMD Biosciences, Inc., 10394 Pacific Center Court, San Diego, CA 92121, USA

3Department of Biochemistry and Genetics, Angers University Hospital, School of Medicine, F-49000 Angers, France

4UMR INSERM, U771-CNRS6214, F-49000 Angers, France

5Center of Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Colket Translational Research Building, Room 6060, 3501 Civic Center Boulevard, Philadelphia, PA 19104-4302, USA

Corresponding author

Citation Information: Biological Chemistry. Volume 391, Issue 10, Pages 1115–1130, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/bc.2010.125, August 2010

Publication History

Published Online:


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.

Keywords: mtDNA; multiplex assay; pathogenic mutations; polymorphisms; SNaPshot

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