Format

Send to

Choose Destination
Am J Hum Genet. 2018 Mar 1;102(3):494-504. doi: 10.1016/j.ajhg.2018.01.020. Epub 2018 Feb 22.

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

Collaborators (166)

Adams DR, Alejandro ME, Allard P, Azamian MS, Bacino CA, Balasubramanyam A, Barseghyan H, Batzli GF, Beggs AH, Behnam B, Bican A, Bick DP, Birch CL, Bonner D, Boone BE, Bostwick BL, Briere LC, Brown DM, Brush M, Burke EA, Burrage LC, Chen S, Clark GD, Coakley TR, Cogan JD, Cooper CM, Cope H, Craigen WJ, D'Souza P, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dillon A, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Douine ED, Draper DD, Eckstein DJ, Emrick LT, Eng CM, Eskin A, Esteves C, Estwick T, Ferreira C, Fogel BL, Friedman ND, Gahl WA, Glanton E, Godfrey RA, Goldstein DB, Gould SE, Gourdine JF, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, Handley LH, Herzog MR, Holm IA, Hom J, Howerton EM, Huang Y, Jacob HJ, Jain M, Jiang YH, Johnston JM, Jones AL, Kohane IS, Krasnewich DM, Krieg EL, Krier JB, Lalani SR, Lau CC, Lazar J, Lee BH, Lee H, Levy SE, Lewis RA, Lincoln SA, Lipson A, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Marom R, Martínez-Agosto JA, Marwaha S, May T, McConkie-Rosell A, McCormack CE, McCray AT, Might M, Moretti PM, Morimoto M, Mulvihill JJ, Murphy JL, Muzny DM, Nehrebecky ME, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Pallais JC, Palmer CGS, Papp JC, Parker NH, Pena LDM, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Reuter CM, Robertson AK, Rodan LH, Rosenfeld JA, Sampson JB, Samson SL, Schoch K, Schroeder MC, Scott DA, Sharma P, Shashi V, Silverman EK, Sinsheimer JS, Smith KS, Spillmann RC, Splinter K, Stoler JM, Stong N, Sullivan JA, Sweetser DA, Tifft CJ, Toro C, Tran AA, Urv TK, Valivullah ZM, Vilain E, Vogel TP, Wahl CE, Walley NM, Walsh CA, Ward PA, Waters KM, Westerfield M, Wise AL, Wolfe LA, Worthey EA, Yamamoto S, Yang Y, Yu G, Zastrow DB, Zheng A.

Author information

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: wheelerm@stanford.edu.

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

PMID:
29478781
PMCID:
PMC6117612
DOI:
10.1016/j.ajhg.2018.01.020
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center