Journal article
Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming
M Picard, J Zhang, S Hancock, O Derbeneva, R Golhar, P Golik, S O'Hearn, S Levy, P Potluri, M Lvova, A Davila, CS Lin, JC Perin, EF Rappaport, H Hakonarson, IA Trounce, V Procaccio, DC Wallace
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2014
Abstract
Variation in the intracellular percentage of normal and mutant mitochondrial DNAs (mtDNA) (heteroplasmy) can be associated with phenotypic heterogeneity in mtDNA diseases. Individuals that inherit the common disease-causing mtDNA tRNALeu(UUR)3243A>G mutation and harbor ~10-30% 3243G mutant mtDNAs manifest diabetes and occasionally autism; individuals with ~50-90% mutant mtDNAs manifest encephalomyopathies; and individuals with ~90-100% mutant mtDNAs face perinatal lethality. To determine the basis of these abrupt phenotypic changes, we generated somatic cell cybrids harboring increasing levels of the 3243G mutant and analyzed the associated cellular phenotypes and nuclear DNA (nDNA) and mtDN..
View full abstractGrants
Awarded by National Institute of Neurological Disorders and Stroke
Funding Acknowledgements
The authors thank Katelyn Sweeney and the University of Pennsylvania EM Core Facilities for technical assistance on parts of this project. This work was supported by Simon Foundation Grant 205844 and by National Institutes of Health Grants NS21328, NS070298, AG24373, and DK73691 (to D. C. W.). M. P. is supported by a postdoctoral fellowship from the Canadian Institute of Health Research Institute of Neuroscience as part of the Canadian Epigenetics, Environment, and Health Research Consortium.