Case Reports

. 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

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, Affiliations

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: wheelerm@stanford.edu.

PMID: 29478781
PMCID: PMC6117612
DOI: 10.1016/j.ajhg.2018.01.020

Case Reports

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

Monika Oláhová et al. Am J Hum Genet. 2018.

. 2018 Mar 1;102(3):494-504.

doi: 10.1016/j.ajhg.2018.01.020. Epub 2018 Feb 22.

Authors

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: wheelerm@stanford.edu.

PMID: 29478781
PMCID: PMC6117612
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 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.

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Figures

**Figure 1**
Molecular Genetic Studies of *ATP5F1D* Variants (A) Pedigrees and sequencing chromatograms of the two affected families show segregation of the homozygous *ATP5F1D* variant c.245C>T (p.Pro82Leu) in subject 1 and c.317T>G (p.Val106Gly) in subject 2. (B) Multiple-sequence alignment confirms evolutionary conservation of p.Pro82Leu and p.Val106Gly in both human and flies. (C) SWISS-MODEL-predicted structure of wild-type, p.Pro82Leu, and p.Val106Gly ATP5F1D.

**Figure 2**
Biallelic Variants in *ATP5F1D* Impair the Steady-State Amounts of the F₁F_O ATP Synthase Complex and Subunits Immunoblot and BN-PAGE analysis were carried out on subject cultured skin fibroblasts and skeletal muscle samples as previously described., , SDS-PAGE and immunoblot analysis of whole-cell lysates (40 μg) isolated from cultured skin fibroblasts of affected subjects 1 (S1) and 2 (S2) and age-matched control individuals show (A) the steady-state amounts of complex V subunits (ATP5F1A, ATP5F1B, ATP5F1D, and ATP5PO) and (B) the amounts of individual OXPHOS complex subunits. One-dimensional BN-PAGE analysis was performed for assembled OXPHOS complexes in n-dodecyl-β-D-maltoside (DDM; 850520P, Sigma)-solubilized mitochondrial extracts isolated from control, S1, and S2 fibroblasts (C). Steady-state amounts (D) and assembly (E) of OXPHOS complexes and subunits in DDM-solubilized mitochondrial extracts from control and subject 2 skeletal muscle demonstrate a decrease in complex V. In (C) and (E), mitochondrial lysates (100 μg) were loaded on a 4%–16% native gel (Life Technologies), and then protein complexes were immobilized onto polyvinylidene difluoride membranes and subjected to immunoblotting with the indicated OXPHOS-subunit-specific antibodies. In (A)–(E), nuclear-encoded SDHA (ab14715, Abcam) or porin (VDAC1, ab14734, Abcam) was used as a loading control. Abbreviations are as follows: BN, blue native; CI, complex I; CII, complex II; CIII, complex III; CIV, complex IV; and CV, complex V.

**Figure 3**
Subject-Derived Cells Carrying a c.245C>T (p.Pro82Leu) *ATP5F1D* Variant Exhibit a Decreased Number of Cristae (A) TEM of cultured skin fibroblasts from an unaffected control individual and subject 1 (S1) (p.Pro82Leu). (B) TEM of iPSC-derived cardiomyocytes. Red arrows show mitochondria devoid of cristae in cells from affected individual S1 (p.Pro82Leu). Black arrows indicate nascent sarcomeres. Scale bar: 500 nm. (C) Quantification of mitochondrial size in control and subject 1 (p.Pro82Leu) fibroblasts. Error bars indicate SEM, and p values were calculated by Student’s t test. N.S. indicates not statistically significant. (D) Quantification of the number of cristae per mitochondrion in control and subject 1 (p.Pro82Leu) fibroblasts. Error bars indicate SEM, and p values were calculated by Student’s t test (^∗∗∗p < 0.001). (E) Quantification of the mitochondrial area in control and subject 1 (p.Pro82Leu) iPSC-derived cardiomyocytes. Quartiles and minimum and maximum values are shown, and p values were calculated by an unpaired two-tailed t test (p = 0.03). (F) Quantification of the number of cristae per mitochondrion in control and subject 1 (p.Pro82Leu) iPSC-derived cardiomyocytes. Quartiles and minimum and maximum values are shown, and p values were calculated by an unpaired t test (p < 0.001).

**Figure 4**
ATP5F1D p.Pro82Leu and p.Val106Gly Are Partial Loss-of-Function Variants (A) The observed/expected ratio of flies shows the rescue of lethality by the human genes including both variants in the *Drosophila* null background. (B and C) Expression of *ATPsyn*δ RNAi by *ey-Gal4* caused pupal lethality and an extremely reduced head size (*ey-Gal4/UAS-ATPsynδ RNAi; UAS-LacZ/+*) (C), whereas control animals without the *ey-Gal4* driver (*UAS-ATPsynδ RNAi/+; UAS-LacZ*) showed normal head development (B). (D–F) Light micrographs of fly eyes expressing *ey-Gal4* and *ATPsynδ* RNAi together with *UAS-ATP5F1D*^WT (D), *UAS-ATP5F1D*^P82L (E), or *UAS-ATP5F1D*^V106G (F). We found that expression of *ATP5F1D*^WT rescued the tiny-head phenotype caused by knockdown of *ATPsynδ* (D). However, a portion of adult flies expressing *ATPsynδ* RNAi together with *ATP5F1D*^P82L or *ATP5F1D*^V106G exhibited abnormal eye morphology, including glassy eyes, small eyes, and bar eyes (E and F). Quantification of the phenotypes shows that expression of *ATP5F1D*^V106G causes more severe defects than *ATP5F1D*^P82L (J). (G–I) Light micrographs of fly antenna expressing *ey-Gal4* and *ATPsynδ* RNAi together with *UAS-ATP5F1D*^WT (G), *UAS-ATP5F1D*^P82L (H), or *UAS-ATP5F1D*^V106G (I). (K) Quantification of the antenna morphology phenotypes described in (G)–(I).

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References

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

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

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