• N. Engl. J. Med. · Oct 2020

    Case Reports

    Purifying Selection against Pathogenic Mitochondrial DNA in Human T Cells.

    • Melissa A Walker, Caleb A Lareau, Leif S Ludwig, Amel Karaa, Vijay G Sankaran, Aviv Regev, and Vamsi K Mootha.
    • From the Departments of Molecular Biology (M.A.W., V.K.M.), Neurology (M.A.W.), and Medicine (V.K.M) and the Genetics Unit, Department of Pediatrics (A.K.), Massachusetts General Hospital, Howard Hughes Medical Institute (M.A.W., A.R., V.K.M.), the Division of Hematology-Oncology, Boston Children's Hospital (C.A.L., L.S.L., V.G.S.), the Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School (C.A.L., L.S.L., V.G.S.), the Department of Systems Biology, Harvard Medical School (V.K.M.), and Harvard Medical School (M.A.W., A.K.), Boston, and the Klarman Cell Observatory (L.S.L., A.R.), Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard (M.A.W., C.A.L., V.G.S., V.K.M.), the Harvard Stem Cell Institute (V.G.S.), and the Department of Biology and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology (A.R.), Cambridge - both in Massachusetts.
    • N. Engl. J. Med. 2020 Oct 15; 383 (16): 1556-1563.

    AbstractMany 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.).Copyright © 2020 Massachusetts Medical Society.

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