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

Monika Oláhová; Wan Hee Yoon; Kyle Thompson; Sharayu Jangam; Liliana Fernandez; Jean M Davidson; Jennifer E Kyle; Megan E Grove; Dianna G Fisk; Jennefer N Kohler; Matthew Holmes; Annika M Dries; Yong Huang; Chunli Zhao; Kévin Contrepois; Zachary Zappala; Laure Frésard; Daryl Waggott; Erika M Zink; Young-Mo Kim; Heino M Heyman; Kelly G Stratton; Bobbie-Jo M Webb-Robertson; Undiagnosed Diseases Network; Michael Snyder; Jason D Merker; Stephen B Montgomery; Paul G Fisher; René G Feichtinger; Johannes A Mayr; Julie Hall; Ines A Barbosa; Michael A Simpson; Charu Deshpande; Katrina M Waters; David M Koeller; Thomas O Metz; Andrew A Morris; Susan Schelley; Tina Cowan; Marisa W Friederich; Robert McFarland; Johan L K Van Hove; Gregory M Enns; Shinya Yamamoto; Euan A Ashley; Michael F Wangler; Robert W Taylor; Hugo J Bellen; Jonathan A Bernstein; Matthew T Wheeler

doi:10.1016/j.ajhg.2018.01.020

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. Epub 2018 Feb 22.

Authors

Monika Oláhová¹, Wan Hee Yoon², Kyle Thompson¹, Sharayu Jangam³, Liliana Fernandez⁴, Jean M Davidson⁴, Jennifer E Kyle⁵, Megan E Grove⁶, Dianna G Fisk⁶, Jennefer N Kohler⁴, Matthew Holmes¹, Annika M Dries⁴, Yong Huang⁴, Chunli Zhao⁴, Kévin Contrepois⁷, Zachary Zappala⁷, Laure Frésard⁸, Daryl Waggott⁴, Erika M Zink⁵, Young-Mo Kim⁵, Heino M Heyman⁵, Kelly G Stratton⁹, Bobbie-Jo M Webb-Robertson⁹; Undiagnosed Diseases Network; Michael Snyder⁷, Jason D Merker¹⁰, Stephen B Montgomery¹¹, Paul G Fisher⁴, René G Feichtinger¹², Johannes A Mayr¹², Julie Hall¹³, Ines A Barbosa¹⁴, Michael A Simpson¹⁴, Charu Deshpande¹⁵, Katrina M Waters⁵, David M Koeller¹⁶, Thomas O Metz⁵, Andrew A Morris¹⁷, Susan Schelley¹⁸, Tina Cowan⁸, Marisa W Friederich¹⁹, Robert McFarland¹, Johan L K Van Hove¹⁹, Gregory M Enns¹⁸, Shinya Yamamoto²⁰, Euan A Ashley²¹, Michael F Wangler²², Robert W Taylor¹, Hugo J Bellen²³, Jonathan A Bernstein²⁴, Matthew T Wheeler²⁵

Collaborators

Undiagnosed Diseases Network:
David R Adams, Mercedes E Alejandro, Patrick Allard, Mahshid S Azamian, Carlos A Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F Batzli, Alan H Beggs, Babak Behnam, Anna Bican, David P Bick, Camille L Birch, Devon Bonner, Braden E Boone, Bret L Bostwick, Lauren C Briere, Donna M Brown, Matthew Brush, Elizabeth A Burke, Lindsay C Burrage, Shan Chen, Gary D Clark, Terra R Coakley, Joy D Cogan, Cynthia M Cooper, Heidi Cope, William J Craigen, Precilla D'Souza, Mariska Davids, Jyoti G Dayal, Esteban C Dell'Angelica, Shweta U Dhar, Ani Dillon, Katrina M Dipple, Laurel A Donnell-Fink, Naghmeh Dorrani, Daniel C Dorset, Emilie D Douine, David D Draper, David J Eckstein, Lisa T Emrick, Christine M Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos Ferreira, Brent L Fogel, Noah D Friedman, William A Gahl, Emily Glanton, Rena A Godfrey, David B Goldstein, Sarah E Gould, Jean-Philippe F Gourdine, Catherine A Groden, Andrea L Gropman, Melissa Haendel, Rizwan Hamid, Neil A Hanchard, Lori H Handley, Matthew R Herzog, Ingrid A Holm, Jason Hom, Ellen M Howerton, Yong Huang, Howard J Jacob, Mahim Jain, Yong-Hui Jiang, Jean M Johnston, Angela L Jones, Isaac S Kohane, Donna M Krasnewich, Elizabeth L Krieg, Joel B Krier, Seema R Lalani, C Christopher Lau, Jozef Lazar, Brendan H Lee, Hane Lee, Shawn E Levy, Richard A Lewis, Sharyn A Lincoln, Allen Lipson, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, Marta M Majcherska, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Thomas C Markello, Ronit Marom, Julian A Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E McCormack, Alexa T McCray, Matthew Might, Paolo M Moretti, Marie Morimoto, John J Mulvihill, Jennifer L Murphy, Donna M Muzny, Michele E Nehrebecky, Stan F Nelson, J Scott Newberry, John H Newman, Sarah K Nicholas, Donna Novacic, Jordan S Orange, J Carl Pallais, Christina G S Palmer, Jeanette C Papp, Neil H Parker, Loren D M Pena, John A Phillips 3rd, Jennifer E Posey, John H Postlethwait, Lorraine Potocki, Barbara N Pusey, Chloe M Reuter, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Jacinda B Sampson, Susan L Samson, Kelly Schoch, Molly C Schroeder, Daryl A Scott, Prashant Sharma, Vandana Shashi, Edwin K Silverman, Janet S Sinsheimer, Kevin S Smith, Rebecca C Spillmann, Kimberly Splinter, Joan M Stoler, Nicholas Stong, Jennifer A Sullivan, David A Sweetser, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Tiina K Urv, Zaheer M Valivullah, Eric Vilain, Tiphanie P Vogel, Colleen E Wahl, Nicole M Walley, Chris A Walsh, Patricia A Ward, Katrina M Waters, Monte Westerfield, Anastasia L Wise, Lynne A Wolfe, Elizabeth A Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B Zastrow, Allison Zheng

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].

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 F₁F_O 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.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles*
Amino Acid Sequence
Base Sequence
Child
Child, Preschool
Female
Humans
Infant
Infant, Newborn
Loss of Function Mutation / genetics
Male
Metabolic Diseases / genetics*
Mitochondria / metabolism
Mitochondria / ultrastructure
Mitochondrial Proton-Translocating ATPases / chemistry
Mitochondrial Proton-Translocating ATPases / genetics*
Mutation / genetics*
Protein Subunits / chemistry
Protein Subunits / genetics*

Substances

Protein Subunits
Mitochondrial Proton-Translocating ATPases
ATP5F1D protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding