• Rebecca D Ganetzky, Andrew L Markhard, Irene Yee, Sheila Clever, Alan Cahill, Hardik Shah, Zenon Grabarek, Tsz-Leung To, and Vamsi K Mootha.
• From the Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia (R.D.G., I.Y., S.C., A.C.), and the Department of Pediatrics, University of Pennsylvania Perelman School of Medicine (R.D.G.) - both in Philadelphia; and Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston (A.L.M., H.S., Z.G., T.-L.T., V.K.M.), and the Metabolism Program, Broad Institute, Cambridge (A.L.M., H.S., Z.G., T.L.T., V.K.M.) - both in Massachusetts.
• N. Engl. J. Med. 2022 Oct 13; 387 (15): 139514031395-1403.

AbstractWe describe the case of identical twin boys who presented with low body weight despite excessive caloric intake. An evaluation of their fibroblasts showed elevated oxygen consumption and decreased mitochondrial membrane potential. Exome analysis revealed a de novo heterozygous variant in ATP5F1B, which encodes the β subunit of mitochondrial ATP synthase (also called complex V). In yeast, mutations affecting the same region loosen coupling between the proton motive force and ATP synthesis, resulting in high rates of mitochondrial respiration. Expression of the mutant allele in human cell lines recapitulates this phenotype. These data support an autosomal dominant mitochondrial uncoupling syndrome with hypermetabolism. (Funded by the National Institutes of Health.).Copyright © 2022 Massachusetts Medical Society.

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