2. Academic Validation
  3. Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder

  • Am J Hum Genet. 2018 Mar 1;102(3):494-504. doi: 10.1016/j.ajhg.2018.01.020.
Monika Oláhová 1,  Wan Hee Yoon 2,  Kyle Thompson 1,  Sharayu Jangam 3,  Liliana Fernandez 4,  Jean M Davidson 4,  Jennifer E Kyle 5,  Megan E Grove 6,  Dianna G Fisk 6,  Jennefer N Kohler 4,  Matthew Holmes 1,  Annika M Dries 4,  Yong Huang 4,  Chunli Zhao 4,  Kévin Contrepois 7,  Zachary Zappala 7,  Laure Frésard 8,  Daryl Waggott 4,  Erika M Zink 5,  Young-Mo Kim 5,  Heino M Heyman 5,  Kelly G Stratton 9,  Bobbie-Jo M Webb-Robertson 9,  Undiagnosed Diseases Network,  Michael Snyder 7,  Jason D Merker 10,  Stephen B Montgomery 11,  Paul G Fisher 4,  René G Feichtinger 12,  Johannes A Mayr 12,  Julie Hall 13,  Ines A Barbosa 14,  Michael A Simpson 14,  Charu Deshpande 15,  Katrina M Waters 5,  David M Koeller 16,  Thomas O Metz 5,  Andrew A Morris 17,  Susan Schelley 18,  Tina Cowan 8,  Marisa W Friederich 19,  Robert McFarland 1,  Johan L K Van Hove 19,  Gregory M Enns 18,  Shinya Yamamoto 20,  Euan A Ashley 21,  Michael F Wangler 22,  Robert W Taylor 1,  Hugo J Bellen 23,  Jonathan A Bernstein 24,  Matthew T Wheeler 25
Affiliations

Affiliations

  • 1 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  • 2 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA.
  • 5 Biological Sciences Division, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
  • 6 Clinical Genomics Program, Stanford Health Care, Stanford, CA 94305, USA.
  • 7 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 8 Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 9 Computing & Analytics Division, National Security Directorate, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
  • 10 Clinical Genomics Program, Stanford Health Care, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 11 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 12 Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria.
  • 13 Department of Neuroradiology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
  • 14 Department of Medical and Molecular Genetics, King's College London School of Basic and Medical Biosciences, London SE1 9RT, UK.
  • 15 Clinical Genetics Unit, Guys and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK.
  • 16 Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
  • 17 Institute of Human Development, University of Manchester, Manchester M13 9PL, UK; Willink Metabolic Unit, Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
  • 18 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 19 Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado at Denver, Aurora, CO 80045, USA.
  • 20 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
  • 21 Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Clinical Genomics Program, Stanford Health Care, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 22 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 23 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
  • 24 Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 25 Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 29478781 DOI: 10.1016/j.ajhg.2018.01.020
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.

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