@article{972f9982469a474d8efbacf6f562b91d,
title = "Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder",
abstract = "ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.",
keywords = "3-methylglutaric aciduria, ATP synthase, complex V, exome sequencing, fibroblast, hyperammonemia, lactic acidosis, mitochondrial disease, model organism, oxidative phosphorylation",
author = "{Undiagnosed Diseases Network} and Monika Ol{\'a}hov{\'a} and Yoon, {Wan Hee} and Kyle Thompson and Sharayu Jangam and Liliana Fernandez and Davidson, {Jean M.} and Kyle, {Jennifer E.} and Grove, {Megan E.} and Fisk, {Dianna G.} and Kohler, {Jennefer N.} and Matthew Holmes and Dries, {Annika M.} and Yong Huang and Chunli Zhao and K{\'e}vin Contrepois and Zachary Zappala and Laure Fr{\'e}sard and Daryl Waggott and Zink, {Erika M.} and Kim, {Young Mo} and Heyman, {Heino M.} and Stratton, {Kelly G.} and Webb-Robertson, {Bobbie Jo M.} and Adams, {David R.} and Alejandro, {Mercedes E.} and Patrick Allard and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Ashok Balasubramanyam and Hayk Barseghyan and Batzli, {Gabriel F.} and Beggs, {Alan H.} and Babak Behnam and Anna Bican and Bick, {David P.} and Birch, {Camille L.} and Devon Bonner and Boone, {Braden E.} and Bostwick, {Bret L.} and Briere, {Lauren C.} and Brown, {Donna M.} and Matthew Brush and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Shan Chen and Clark, {Gary D.} and Coakley, {Terra R.} and Cogan, {Joy D.} and Melissa Haendel and Koeller, {David M.}",
note = "Funding Information: We thank L. Duraine, Z. Zuo, K. Schulze, A. Chang, and Y. He for technical support. Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination and Office of the NIH Director (award numbers U01HG007708 , U01HG007942 , U01TR001395 , and U54NS093793 ), the NIH National Center for Advancing Translational Sciences ( UL1TR001085 ), the NIH National Center for Research Resources ( S10 RR026780 ), the NIH National Human Genome Research Institute ( P50HG007735 ), the Wellcome Centre for Mitochondrial Research ( 203105/Z/16/Z ), the Medical Research Council Centre for Translational Research in Neuromuscular Disease , the UK Mitochondrial Disease Patient Cohort ( G0800674 ), the Lily Foundation , the UK National Health Service Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children , E-Rare project GENOMIT by the Austrian Science Fonds ( I 2741-B26 ), and the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London. Portions of the metabolomics and lipidomics analyses were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the Department of Energy (DOE) Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory (PNNL). PNNL is operated by Battelle Memorial Institute for the DOE under contract DE-AC05-76RLO1830. M.H. was supported by a Wolfson intercalation bursary award from the UK Royal College of Physicians . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: We thank L. Duraine, Z. Zuo, K. Schulze, A. Chang, and Y. He for technical support. Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination and Office of the NIH Director (award numbers U01HG007708, U01HG007942, U01TR001395, and U54NS093793), the NIH National Center for Advancing Translational Sciences (UL1TR001085), the NIH National Center for Research Resources (S10 RR026780), the NIH National Human Genome Research Institute (P50HG007735), the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council Centre for Translational Research in Neuromuscular Disease, the UK Mitochondrial Disease Patient Cohort (G0800674), the Lily Foundation, the UK National Health Service Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, E-Rare project GENOMIT by the Austrian Science Fonds (I 2741-B26), and the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's and St. Thomas{\textquoteright} NHS Foundation Trust in partnership with King's College London. Portions of the metabolomics and lipidomics analyses were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the Department of Energy (DOE) Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory (PNNL). PNNL is operated by Battelle Memorial Institute for the DOE under contract DE-AC05-76RLO1830. M.H. was supported by a Wolfson intercalation bursary award from the UK Royal College of Physicians. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = mar,
day = "1",
doi = "10.1016/j.ajhg.2018.01.020",
language = "English (US)",
volume = "102",
pages = "494--504",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",
}