Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 383, Issue 16, Pages 1556-1563Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa2001265
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Funding
- Marriott Foundation
- MacCurtain Family, the Tosteson Fund for Medical Discovery, the Massachusetts General Hospital Department of Neurology
- New York Stem Cell Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institutes of Health
- Klarman Cell Observatory
- National Human Genome Research Institute Center of Excellence in Genome Science
- National Center for Advancing Translational Sciences (National Institutes of Health) [UL 1TR002541]
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Many mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA). Patients' cells contain a mixture of mutant and nonmutant mtDNA (a phenomenon called heteroplasmy). The proportion of mutant mtDNA varies across patients and among tissues within a patient. We simultaneously assayed single-cell heteroplasmy and cell state in thousands of blood cells obtained from three unrelated patients who had A3243G-associated mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. We observed a broad range of heteroplasmy across all cell types but also found markedly reduced heteroplasmy in T cells, a finding consistent with purifying selection within this lineage. We observed this pattern in six additional patients who had heteroplasmic A3243G without strokelike episodes. (Funded by the Marriott Foundation and others.) Most mitochondrial diseases are caused by mutations in mitochondrial DNA. A new type of genomic analysis provides evidence of selection against mutant mitochondria DNA in human T cells.
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