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; 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; 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 III; 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; 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; 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; 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

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 KimHeino M. Heyman, Kelly G. Stratton, Bobbie-Jo M. Webb-Robertson, 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, 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 III, 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, 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, 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, Euan A. Ashley, Michael F. Wangler, Robert W. Taylor, Hugo J. Bellen, Jonathan A. Bernstein, Matthew T. Wheeler

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

56 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Human Genetics
Early online date	22 Feb 2018
DOIs	https://doi.org/10.1016/j.ajhg.2018.01.020
Publication status	E-pub ahead of print - 22 Feb 2018

Keywords

mitochondrial disease
complex V
ATP synthase
exome sequencing
oxidative phosphorylation
lactic acidosis
hyperammonemia
3-methylglutaric aciduria
model organism
fibroblast

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2018.01.020Licence: CC BY

Cite this

Oláhová, M., Yoon, W. H., Thompson, K., Jangam, S., Fernandez, L., Davidson, J. M., Kyle, J. E., Grove, M. E., Fisk, D. G., Kohler, J. N., Holmes, M., Dries, A. M., Huang, Y., Zhao, C., Contrepois, K., Zappala, Z., Frésard, L., Waggott, D., Zink, E. M., ... Wheeler, M. T. (2018). Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. American Journal of Human Genetics. Advance online publication. https://doi.org/10.1016/j.ajhg.2018.01.020

@article{09c5b802d567461f94d5b13e8de03804,

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 = "mitochondrial disease, complex V, ATP synthase, exome sequencing, oxidative phosphorylation, lactic acidosis, hyperammonemia, 3-methylglutaric aciduria, model organism, fibroblast",

author = "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 Young-Mo Kim 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 Cooper, {Cynthia M.} and Heidi Cope and Craigen, {William J.} and Precilla D{\textquoteright}Souza and Mariska Davids and Dayal, {Jyoti G.} and Dell{\textquoteright}Angelica, {Esteban C.} and Dhar, {Shweta U.} and Ani Dillon and Dipple, {Katrina M.} and Donnell-Fink, {Laurel A.} and Naghmeh Dorrani and Dorset, {Daniel C.} and Douine, {Emilie D.} and Draper, {David D.} and Eckstein, {David J.} and Emrick, {Lisa T.} and Eng, {Christine M.} and Ascia Eskin and Cecilia Esteves and Tyra Estwick and Carlos Ferreira and Fogel, {Brent L.} and Friedman, {Noah D.} and Gahl, {William A.} and Emily Glanton and Godfrey, {Rena A.} and Goldstein, {David B.} and Gould, {Sarah E.} and Gourdine, {Jean-Philippe F.} and Groden, {Catherine A.} and Gropman, {Andrea L.} and Melissa Haendel and Rizwan Hamid and Hanchard, {Neil A.} and Handley, {Lori H.} and Herzog, {Matthew R.} and Holm, {Ingrid A.} and Jason Hom and Howerton, {Ellen M.} and Jacob, {Howard J.} and Mahim Jain and Yong-hui Jiang and Johnston, {Jean M.} and Jones, {Angela L.} and Kohane, {Isaac S.} and Krasnewich, {Donna M.} and Krieg, {Elizabeth L.} and Krier, {Joel B.} and Lalani, {Seema R.} and Lau, {C. Christopher} and Jozef Lazar and Lee, {Brendan H.} and Hane Lee and Levy, {Shawn E.} and Lewis, {Richard A.} and Lincoln, {Sharyn A.} and Allen Lipson and Loo, {Sandra K.} and Joseph Loscalzo and Maas, {Richard L.} and Macnamara, {Ellen F.} and MacRae, {Calum A.} and Maduro, {Valerie V.} and Majcherska, {Marta M.} and Malicdan, {May Christine V.} and Mamounas, {Laura A.} and Manolio, {Teri A.} and Markello, {Thomas C.} and Ronit Marom and Mart{\'i}nez-Agosto, {Julian A.} and Shruti Marwaha and Thomas May and Allyn McConkie-Rosell and McCormack, {Colleen E.} and McCray, {Alexa T.} and Matthew Might and Moretti, {Paolo M.} and Marie Morimoto and Mulvihill, {John J.} and Murphy, {Jennifer L.} and Muzny, {Donna M.} and Nehrebecky, {Michele E.} and Nelson, {Stan F.} and Newberry, {J. Scott} and Newman, {John H.} and Nicholas, {Sarah K.} and Donna Novacic and Orange, {Jordan S.} and Pallais, {J. Carl} and Palmer, {Christina G.S.} and Papp, {Jeanette C.} and Parker, {Neil H.} and Pena, {Loren D.M.} and {Phillips III}, {John A.} and Posey, {Jennifer E.} and Postlethwait, {John H.} and Lorraine Potocki and Pusey, {Barbara N.} and Reuter, {Chloe M.} and Robertson, {Amy K.} and Rodan, {Lance H.} and Rosenfeld, {Jill A.} and Sampson, {Jacinda B.} and Samson, {Susan L.} and Kelly Schoch and Schroeder, {Molly C.} and Scott, {Daryl A.} and Prashant Sharma and Vandana Shashi and Silverman, {Edwin K.} and Sinsheimer, {Janet S.} and Smith, {Kevin S.} and Spillmann, {Rebecca C.} and Kimberly Splinter and Stoler, {Joan M.} and Nicholas Stong and Sullivan, {Jennifer A.} and Sweetser, {David A.} and Tifft, {Cynthia J.} and Camilo Toro and Tran, {Alyssa A.} and Urv, {Tiina K.} and Valivullah, {Zaheer M.} and Eric Vilain and Vogel, {Tiphanie P.} and Wahl, {Colleen E.} and Walley, {Nicole M.} and Walsh, {Chris A.} and Ward, {Patricia A.} and Waters, {Katrina M.} and Monte Westerfield and Wise, {Anastasia L.} and Wolfe, {Lynne A.} and Worthey, {Elizabeth A.} and Shinya Yamamoto and Yaping Yang and Guoyun Yu and Zastrow, {Diane B.} and Allison Zheng and Michael Snyder and Merker, {Jason D.} and Montgomery, {Stephen B.} and Fisher, {Paul G.} and Feichtinger, {Ren{\'e} G.} and Mayr, {Johannes A.} and Julie Hall and Barbosa, {Ines A.} and Simpson, {Michael A.} and Charu Deshpande and Koeller, {David M.} and Metz, {Thomas O.} and Morris, {Andrew A.} and Susan Schelley and Tina Cowan and Friederich, {Marisa W.} and Robert McFarland and {Van Hove}, {Johan L.K.} and Enns, {Gregory M.} and Ashley, {Euan A.} and Wangler, {Michael F.} and Taylor, {Robert W.} and Bellen, {Hugo J.} and Bernstein, {Jonathan A.} and Wheeler, {Matthew T.}",

year = "2018",

month = feb,

day = "22",

doi = "10.1016/j.ajhg.2018.01.020",

language = "English",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Elsevier",

}

Oláhová, M, Yoon, WH, Thompson, K, Jangam, S, Fernandez, L, Davidson, JM, Kyle, JE, Grove, ME, Fisk, DG, Kohler, JN, Holmes, M, Dries, AM, Huang, Y, Zhao, C, Contrepois, K, Zappala, Z, Frésard, L, Waggott, D, Zink, EM, Kim, Y-M, Heyman, HM, Stratton, KG, Webb-Robertson, B-JM, 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, J-PF, Groden, CA, Gropman, AL, Haendel, M, Hamid, R, Hanchard, NA, Handley, LH, Herzog, MR, Holm, IA, Hom, J, Howerton, EM, Jacob, HJ, Jain, M, Jiang, Y, 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 III, JA, 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, Snyder, M, Merker, JD, Montgomery, SB, Fisher, PG, Feichtinger, RG, Mayr, JA, Hall, J, Barbosa, IA, Simpson, MA, Deshpande, C, Koeller, DM, Metz, TO, Morris, AA, Schelley, S, Cowan, T, Friederich, MW, McFarland, R, Van Hove, JLK, Enns, GM, Ashley, EA, Wangler, MF, Taylor, RW, Bellen, HJ, Bernstein, JA & Wheeler, MT 2018, 'Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder', American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2018.01.020

TY - JOUR

T1 - Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder

AU - Oláhová, Monika

AU - Yoon, Wan Hee

AU - Thompson, Kyle

AU - Jangam, Sharayu

AU - Fernandez, Liliana

AU - Davidson, Jean M.

AU - Kyle, Jennifer E.

AU - Grove, Megan E.

AU - Fisk, Dianna G.

AU - Kohler, Jennefer N.

AU - Holmes, Matthew

AU - Dries, Annika M.

AU - Huang, Yong

AU - Zhao, Chunli

AU - Contrepois, Kévin

AU - Zappala, Zachary

AU - Frésard, Laure

AU - Waggott, Daryl

AU - Zink, Erika M.

AU - Kim, Young-Mo

AU - Heyman, Heino M.

AU - Stratton, Kelly G.

AU - Webb-Robertson, Bobbie-Jo M.

AU - Adams, David R.

AU - Alejandro, Mercedes E.

AU - Allard, Patrick

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Balasubramanyam, Ashok

AU - Barseghyan, Hayk

AU - Batzli, Gabriel F.

AU - Beggs, Alan H.

AU - Behnam, Babak

AU - Bican, Anna

AU - Bick, David P.

AU - Birch, Camille L.

AU - Bonner, Devon

AU - Boone, Braden E.

AU - Bostwick, Bret L.

AU - Briere, Lauren C.

AU - Brown, Donna M.

AU - Brush, Matthew

AU - Burke, Elizabeth A.

AU - Burrage, Lindsay C.

AU - Chen, Shan

AU - Clark, Gary D.

AU - Coakley, Terra R.

AU - Cogan, Joy D.

AU - Cooper, Cynthia M.

AU - Cope, Heidi

AU - Craigen, William J.

AU - D’Souza, Precilla

AU - Davids, Mariska

AU - Dayal, Jyoti G.

AU - Dell’Angelica, Esteban C.

AU - Dhar, Shweta U.

AU - Dillon, Ani

AU - Dipple, Katrina M.

AU - Donnell-Fink, Laurel A.

AU - Dorrani, Naghmeh

AU - Dorset, Daniel C.

AU - Douine, Emilie D.

AU - Draper, David D.

AU - Eckstein, David J.

AU - Emrick, Lisa T.

AU - Eng, Christine M.

AU - Eskin, Ascia

AU - Esteves, Cecilia

AU - Estwick, Tyra

AU - Ferreira, Carlos

AU - Fogel, Brent L.

AU - Friedman, Noah D.

AU - Gahl, William A.

AU - Glanton, Emily

AU - Godfrey, Rena A.

AU - Goldstein, David B.

AU - Gould, Sarah E.

AU - Gourdine, Jean-Philippe F.

AU - Groden, Catherine A.

AU - Gropman, Andrea L.

AU - Haendel, Melissa

AU - Hamid, Rizwan

AU - Hanchard, Neil A.

AU - Handley, Lori H.

AU - Herzog, Matthew R.

AU - Holm, Ingrid A.

AU - Hom, Jason

AU - Howerton, Ellen M.

AU - Jacob, Howard J.

AU - Jain, Mahim

AU - Jiang, Yong-hui

AU - Johnston, Jean M.

AU - Jones, Angela L.

AU - Kohane, Isaac S.

AU - Krasnewich, Donna M.

AU - Krieg, Elizabeth L.

AU - Krier, Joel B.

AU - Lalani, Seema R.

AU - Lau, C. Christopher

AU - Lazar, Jozef

AU - Lee, Brendan H.

AU - Lee, Hane

AU - Levy, Shawn E.

AU - Lewis, Richard A.

AU - Lincoln, Sharyn A.

AU - Lipson, Allen

AU - Loo, Sandra K.

AU - Loscalzo, Joseph

AU - Maas, Richard L.

AU - Macnamara, Ellen F.

AU - MacRae, Calum A.

AU - Maduro, Valerie V.

AU - Majcherska, Marta M.

AU - Malicdan, May Christine V.

AU - Mamounas, Laura A.

AU - Manolio, Teri A.

AU - Markello, Thomas C.

AU - Marom, Ronit

AU - Martínez-Agosto, Julian A.

AU - Marwaha, Shruti

AU - May, Thomas

AU - McConkie-Rosell, Allyn

AU - McCormack, Colleen E.

AU - McCray, Alexa T.

AU - Might, Matthew

AU - Moretti, Paolo M.

AU - Morimoto, Marie

AU - Mulvihill, John J.

AU - Murphy, Jennifer L.

AU - Muzny, Donna M.

AU - Nehrebecky, Michele E.

AU - Nelson, Stan F.

AU - Newberry, J. Scott

AU - Newman, John H.

AU - Nicholas, Sarah K.

AU - Novacic, Donna

AU - Orange, Jordan S.

AU - Pallais, J. Carl

AU - Palmer, Christina G.S.

AU - Papp, Jeanette C.

AU - Parker, Neil H.

AU - Pena, Loren D.M.

AU - Phillips III, John A.

AU - Posey, Jennifer E.

AU - Postlethwait, John H.

AU - Potocki, Lorraine

AU - Pusey, Barbara N.

AU - Reuter, Chloe M.

AU - Robertson, Amy K.

AU - Rodan, Lance H.

AU - Rosenfeld, Jill A.

AU - Sampson, Jacinda B.

AU - Samson, Susan L.

AU - Schoch, Kelly

AU - Schroeder, Molly C.

AU - Scott, Daryl A.

AU - Sharma, Prashant

AU - Shashi, Vandana

AU - Silverman, Edwin K.

AU - Sinsheimer, Janet S.

AU - Smith, Kevin S.

AU - Spillmann, Rebecca C.

AU - Splinter, Kimberly

AU - Stoler, Joan M.

AU - Stong, Nicholas

AU - Sullivan, Jennifer A.

AU - Sweetser, David A.

AU - Tifft, Cynthia J.

AU - Toro, Camilo

AU - Tran, Alyssa A.

AU - Urv, Tiina K.

AU - Valivullah, Zaheer M.

AU - Vilain, Eric

AU - Vogel, Tiphanie P.

AU - Wahl, Colleen E.

AU - Walley, Nicole M.

AU - Walsh, Chris A.

AU - Ward, Patricia A.

AU - Waters, Katrina M.

AU - Westerfield, Monte

AU - Wise, Anastasia L.

AU - Wolfe, Lynne A.

AU - Worthey, Elizabeth A.

AU - Yamamoto, Shinya

AU - Yang, Yaping

AU - Yu, Guoyun

AU - Zastrow, Diane B.

AU - Zheng, Allison

AU - Snyder, Michael

AU - Merker, Jason D.

AU - Montgomery, Stephen B.

AU - Fisher, Paul G.

AU - Feichtinger, René G.

AU - Mayr, Johannes A.

AU - Hall, Julie

AU - Barbosa, Ines A.

AU - Simpson, Michael A.

AU - Deshpande, Charu

AU - Koeller, David M.

AU - Metz, Thomas O.

AU - Morris, Andrew A.

AU - Schelley, Susan

AU - Cowan, Tina

AU - Friederich, Marisa W.

AU - McFarland, Robert

AU - Van Hove, Johan L.K.

AU - Enns, Gregory M.

AU - Ashley, Euan A.

AU - Wangler, Michael F.

AU - Taylor, Robert W.

AU - Bellen, Hugo J.

AU - Bernstein, Jonathan A.

AU - Wheeler, Matthew T.

PY - 2018/2/22

Y1 - 2018/2/22

N2 - 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.

AB - 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.

KW - mitochondrial disease

KW - complex V

KW - ATP synthase

KW - exome sequencing

KW - oxidative phosphorylation

KW - lactic acidosis

KW - hyperammonemia

KW - 3-methylglutaric aciduria

KW - model organism

KW - fibroblast

U2 - 10.1016/j.ajhg.2018.01.020

DO - 10.1016/j.ajhg.2018.01.020

M3 - Article

SN - 0002-9297

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this