TY - JOUR
T1 - Quantitation of heteroplasmy of mtDNA sequence variants identified in a population of AD patients and controls by array-based resequencing
AU - Coon, Keith D.
AU - Valla, Jon
AU - Szelinger, Szabolics
AU - Schneider, Lonnie E.
AU - Niedzielko, Tracy L.
AU - Brown, Kevin M.
AU - Pearson, John V.
AU - Halperin, Rebecca
AU - Dunckley, Travis
AU - Papassotiropoulos, Andreas
AU - Caselli, Richard J.
AU - Reiman, Eric M.
AU - Stephan, Dietrich A.
N1 - Funding Information:
The authors thank the neurologists, neuropsychologists, and staffs of the participating Arizona ADCC clinical sites (the Mayo Clinic Scottsdale, Sun Health Research Institute, the University of Arizona Health Sciences Center, and the Barrow Neurological Institute) for their invaluable contributions. The authors also to acknowledge Dr. Phillip Stafford for statistical assistance. This work was supported by an ADCC-sponsored pilot grant (Dr. Coon, PI), an ADCC-sponsored pilot grant (Dr. Valla, PI), and an Arizona Alzheimer’s Disease Consortium Grant P30 AG19610 (Dr. Reiman, PI) from the National Institute on Aging.
PY - 2006/8
Y1 - 2006/8
N2 - The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD) has been well documented. Though evidence for the role of mitochondria in AD seems incontrovertible, the impact of mitochondrial DNA (mtDNA) mutations in AD etiology remains controversial. Though mutations in mitochondrially encoded genes have repeatedly been implicated in the pathogenesis of AD, many of these studies have been plagued by lack of replication as well as potential contamination of nuclear-encoded mitochondrial pseudogenes. To assess the role of mtDNA mutations in the pathogenesis of AD, while avoiding the pitfalls of nuclear-encoded mitochondrial pseudogenes encountered in previous investigations and showcasing the benefits of a novel resequencing technology, we sequenced the entire coding region (15,452 bp) of mtDNA from 19 extremely well-characterized AD patients and 18 age-matched, unaffected controls utilizing a new, reliable, high-throughput array-based resequencing technique, the Human MitoChip. High-throughput, array-based DNA resequencing of the entire mtDNA coding region from platelets of 37 subjects revealed the presence of 208 loci displaying a total of 917 sequence variants. There were no statistically significant differences in overall mutational burden between cases and controls, however, 265 independent sites of statistically significant change between cases and controls were identified. Changed sites were found in genes associated with complexes I (30.2%), III (3.0%), IV (33.2%), and V (9.1%) as well as tRNA (10.6%) and rRNA (14.0%). Despite their statistical significance, the subtle nature of the observed changes makes it difficult to determine whether they represent true functional variants involved in AD etiology or merely naturally occurring dissimilarity. Regardless, this study demonstrates the tremendous value of this novel mtDNA resequencing platform, which avoids the pitfalls of erroneously amplifying nuclear-encoded mtDNA pseudogenes, and our proposed analysis paradigm, which utilizes the availability of raw signal intensity values for each of the four potential alleles to facilitate quantitative estimates of mtDNA heteroplasmy. This information provides a potential new target for burgeoning diagnostics and therapeutics that could truly assist those suffering from this devastating disorder.
AB - The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD) has been well documented. Though evidence for the role of mitochondria in AD seems incontrovertible, the impact of mitochondrial DNA (mtDNA) mutations in AD etiology remains controversial. Though mutations in mitochondrially encoded genes have repeatedly been implicated in the pathogenesis of AD, many of these studies have been plagued by lack of replication as well as potential contamination of nuclear-encoded mitochondrial pseudogenes. To assess the role of mtDNA mutations in the pathogenesis of AD, while avoiding the pitfalls of nuclear-encoded mitochondrial pseudogenes encountered in previous investigations and showcasing the benefits of a novel resequencing technology, we sequenced the entire coding region (15,452 bp) of mtDNA from 19 extremely well-characterized AD patients and 18 age-matched, unaffected controls utilizing a new, reliable, high-throughput array-based resequencing technique, the Human MitoChip. High-throughput, array-based DNA resequencing of the entire mtDNA coding region from platelets of 37 subjects revealed the presence of 208 loci displaying a total of 917 sequence variants. There were no statistically significant differences in overall mutational burden between cases and controls, however, 265 independent sites of statistically significant change between cases and controls were identified. Changed sites were found in genes associated with complexes I (30.2%), III (3.0%), IV (33.2%), and V (9.1%) as well as tRNA (10.6%) and rRNA (14.0%). Despite their statistical significance, the subtle nature of the observed changes makes it difficult to determine whether they represent true functional variants involved in AD etiology or merely naturally occurring dissimilarity. Regardless, this study demonstrates the tremendous value of this novel mtDNA resequencing platform, which avoids the pitfalls of erroneously amplifying nuclear-encoded mtDNA pseudogenes, and our proposed analysis paradigm, which utilizes the availability of raw signal intensity values for each of the four potential alleles to facilitate quantitative estimates of mtDNA heteroplasmy. This information provides a potential new target for burgeoning diagnostics and therapeutics that could truly assist those suffering from this devastating disorder.
KW - Alzheimer's disease
KW - Heteroplasmy
KW - Microarray
KW - Mitochondria
KW - Resequencing
UR - http://www.scopus.com/inward/record.url?scp=33748201067&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33748201067&partnerID=8YFLogxK
U2 - 10.1016/j.mito.2006.07.002
DO - 10.1016/j.mito.2006.07.002
M3 - Article
C2 - 16920408
AN - SCOPUS:33748201067
SN - 1567-7249
VL - 6
SP - 194
EP - 210
JO - Mitochondrion
JF - Mitochondrion
IS - 4
ER -