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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 F 1F 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 episodicmore » metabolic decompensation.« less

Authors:
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Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH); Wellcome Centre; Austrian Science Fonds; UK National Health Service
Contributing Org.:
Undiagnosed Diseases Network Consortia
OSTI Identifier:
1423326
Grant/Contract Number:
AC0576RL01830
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
American Journal of Human Genetics
Additional Journal Information:
Journal Volume: 102; Journal Issue: 3; Journal ID: ISSN 0002-9297
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; mitochondrial disease; complex V; ATP synthase; exome sequencing; oxidative phosphorylation; lactic acidosis; hyperammonemia; 3-methylglutaric aciduria; model organism; fibroblast

Citation Formats

Oláhová, Monika, Yoon, Wan Hee, Thompson, Kyle, Jangam, Sharayu, Fernandez, Liliana, Davidson, Jean M., Kyle, Jennifer E., Grove, Megan E., Fisk, Dianna G., Kohler, Jennefer N., Holmes, Matthew, Dries, Annika M., Huang, Yong, Zhao, Chunli, Contrepois, Kévin, Zappala, Zachary, Frésard, Laure, Waggott, Daryl, Zink, Erika M., Kim, Young-Mo, Heyman, Heino M., Stratton, Kelly G., Webb-Robertson, Bobbie-Jo M., Snyder, Michael, Merker, Jason D., Montgomery, Stephen B., Fisher, Paul G., Feichtinger, René G., Mayr, Johannes A., Hall, Julie, Barbosa, Ines A., Simpson, Michael A., Deshpande, Charu, Waters, Katrina M., Koeller, David M., Metz, Thomas O., Morris, Andrew A., Schelley, Susan, Cowan, Tina, Friederich, Marisa W., McFarland, Robert, Van Hove, Johan L. K., Enns, Gregory M., Yamamoto, Shinya, Ashley, Euan A., Wangler, Michael F., Taylor, Robert W., Bellen, Hugo J., Bernstein, Jonathan A., Wheeler, Matthew T., Adams, David R., Alejandro, Mercedes E., Allard, Patrick, Azamian, Mahshid S., Bacino, Carlos A., Balasubramanyam, Ashok, Barseghyan, Hayk, Batzli, Gabriel F., Beggs, Alan H., Behnam, Babak, Bican, Anna, Bick, David P., Birch, Camille L., Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Briere, Lauren C., Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Chen, Shan, Clark, Gary D., Coakley, Terra R., Cogan, Joy D., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., D’Souza, Precilla, Davids, Mariska, Dayal, Jyoti G., Dell’Angelica, Esteban C., Dhar, Shweta U., Dillon, Ani, Dipple, Katrina M., Donnell-Fink, Laurel A., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Eskin, Ascia, Esteves, Cecilia, Estwick, Tyra, Ferreira, Carlos, Fogel, Brent L., Friedman, Noah D., Gahl, William A., Glanton, Emily, Godfrey, Rena A., Goldstein, David B., Gould, Sarah E., Gourdine, Jean-Philippe F., Groden, Catherine A., Gropman, Andrea L., Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A., Handley, Lori H., Herzog, Matthew R., Holm, Ingrid A., Hom, Jason, Howerton, Ellen M., Huang, Yong, Jacob, Howard J., Jain, Mahim, Jiang, Yong-hui, Johnston, Jean M., Jones, Angela L., Kohane, Isaac S., Krasnewich, Donna M., Krieg, Elizabeth L., Krier, Joel B., Lalani, Seema R., Lau, C. Christopher, Lazar, Jozef, Lee, Brendan H., Lee, Hane, Levy, Shawn E., Lewis, Richard A., Lincoln, Sharyn A., Lipson, Allen, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Markello, Thomas C., Marom, Ronit, Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Might, Matthew, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murphy, Jennifer L., Muzny, Donna M., Nehrebecky, Michele E., Nelson, Stan F., Newberry, J. Scott, Newman, John H., Nicholas, Sarah K., Novacic, Donna, Orange, Jordan S., Pallais, J. Carl, Palmer, Christina G. S., Papp, Jeanette C., Parker, Neil H., Pena, Loren D. M., Phillips, John A., Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Reuter, Chloe M., Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Sampson, Jacinda B., Samson, Susan L., Schoch, Kelly, Schroeder, Molly C., Scott, Daryl A., Sharma, Prashant, Shashi, Vandana, Silverman, Edwin K., Sinsheimer, Janet S., Smith, Kevin S., Spillmann, Rebecca C., Splinter, Kimberly, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sweetser, David A., Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Valivullah, Zaheer M., Vilain, Eric, Vogel, Tiphanie P., Wahl, Colleen E., Walley, Nicole M., Walsh, Chris A., Ward, Patricia A., Waters, Katrina M., Westerfield, Monte, Wise, Anastasia L., Wolfe, Lynne A., Worthey, Elizabeth A., Yamamoto, Shinya, Yang, Yaping, Yu, Guoyun, Zastrow, Diane B., and Zheng, Allison. Biallelic Mutations in ATP5F1D , which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. United States: N. p., 2018. Web. doi:10.1016/j.ajhg.2018.01.020.
Oláhová, Monika, Yoon, Wan Hee, Thompson, Kyle, Jangam, Sharayu, Fernandez, Liliana, Davidson, Jean M., Kyle, Jennifer E., Grove, Megan E., Fisk, Dianna G., Kohler, Jennefer N., Holmes, Matthew, Dries, Annika M., Huang, Yong, Zhao, Chunli, Contrepois, Kévin, Zappala, Zachary, Frésard, Laure, Waggott, Daryl, Zink, Erika M., Kim, Young-Mo, Heyman, Heino M., Stratton, Kelly G., Webb-Robertson, Bobbie-Jo M., Snyder, Michael, Merker, Jason D., Montgomery, Stephen B., Fisher, Paul G., Feichtinger, René G., Mayr, Johannes A., Hall, Julie, Barbosa, Ines A., Simpson, Michael A., Deshpande, Charu, Waters, Katrina M., Koeller, David M., Metz, Thomas O., Morris, Andrew A., Schelley, Susan, Cowan, Tina, Friederich, Marisa W., McFarland, Robert, Van Hove, Johan L. K., Enns, Gregory M., Yamamoto, Shinya, Ashley, Euan A., Wangler, Michael F., Taylor, Robert W., Bellen, Hugo J., Bernstein, Jonathan A., Wheeler, Matthew T., Adams, David R., Alejandro, Mercedes E., Allard, Patrick, Azamian, Mahshid S., Bacino, Carlos A., Balasubramanyam, Ashok, Barseghyan, Hayk, Batzli, Gabriel F., Beggs, Alan H., Behnam, Babak, Bican, Anna, Bick, David P., Birch, Camille L., Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Briere, Lauren C., Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Chen, Shan, Clark, Gary D., Coakley, Terra R., Cogan, Joy D., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., D’Souza, Precilla, Davids, Mariska, Dayal, Jyoti G., Dell’Angelica, Esteban C., Dhar, Shweta U., Dillon, Ani, Dipple, Katrina M., Donnell-Fink, Laurel A., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Eskin, Ascia, Esteves, Cecilia, Estwick, Tyra, Ferreira, Carlos, Fogel, Brent L., Friedman, Noah D., Gahl, William A., Glanton, Emily, Godfrey, Rena A., Goldstein, David B., Gould, Sarah E., Gourdine, Jean-Philippe F., Groden, Catherine A., Gropman, Andrea L., Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A., Handley, Lori H., Herzog, Matthew R., Holm, Ingrid A., Hom, Jason, Howerton, Ellen M., Huang, Yong, Jacob, Howard J., Jain, Mahim, Jiang, Yong-hui, Johnston, Jean M., Jones, Angela L., Kohane, Isaac S., Krasnewich, Donna M., Krieg, Elizabeth L., Krier, Joel B., Lalani, Seema R., Lau, C. Christopher, Lazar, Jozef, Lee, Brendan H., Lee, Hane, Levy, Shawn E., Lewis, Richard A., Lincoln, Sharyn A., Lipson, Allen, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Markello, Thomas C., Marom, Ronit, Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Might, Matthew, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murphy, Jennifer L., Muzny, Donna M., Nehrebecky, Michele E., Nelson, Stan F., Newberry, J. Scott, Newman, John H., Nicholas, Sarah K., Novacic, Donna, Orange, Jordan S., Pallais, J. Carl, Palmer, Christina G. S., Papp, Jeanette C., Parker, Neil H., Pena, Loren D. M., Phillips, John A., Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Reuter, Chloe M., Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Sampson, Jacinda B., Samson, Susan L., Schoch, Kelly, Schroeder, Molly C., Scott, Daryl A., Sharma, Prashant, Shashi, Vandana, Silverman, Edwin K., Sinsheimer, Janet S., Smith, Kevin S., Spillmann, Rebecca C., Splinter, Kimberly, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sweetser, David A., Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Valivullah, Zaheer M., Vilain, Eric, Vogel, Tiphanie P., Wahl, Colleen E., Walley, Nicole M., Walsh, Chris A., Ward, Patricia A., Waters, Katrina M., Westerfield, Monte, Wise, Anastasia L., Wolfe, Lynne A., Worthey, Elizabeth A., Yamamoto, Shinya, Yang, Yaping, Yu, Guoyun, Zastrow, Diane B., & Zheng, Allison. Biallelic Mutations in ATP5F1D , which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. United States. doi:10.1016/j.ajhg.2018.01.020.
Oláhová, Monika, Yoon, Wan Hee, Thompson, Kyle, Jangam, Sharayu, Fernandez, Liliana, Davidson, Jean M., Kyle, Jennifer E., Grove, Megan E., Fisk, Dianna G., Kohler, Jennefer N., Holmes, Matthew, Dries, Annika M., Huang, Yong, Zhao, Chunli, Contrepois, Kévin, Zappala, Zachary, Frésard, Laure, Waggott, Daryl, Zink, Erika M., Kim, Young-Mo, Heyman, Heino M., Stratton, Kelly G., Webb-Robertson, Bobbie-Jo M., Snyder, Michael, Merker, Jason D., Montgomery, Stephen B., Fisher, Paul G., Feichtinger, René G., Mayr, Johannes A., Hall, Julie, Barbosa, Ines A., Simpson, Michael A., Deshpande, Charu, Waters, Katrina M., Koeller, David M., Metz, Thomas O., Morris, Andrew A., Schelley, Susan, Cowan, Tina, Friederich, Marisa W., McFarland, Robert, Van Hove, Johan L. K., Enns, Gregory M., Yamamoto, Shinya, Ashley, Euan A., Wangler, Michael F., Taylor, Robert W., Bellen, Hugo J., Bernstein, Jonathan A., Wheeler, Matthew T., Adams, David R., Alejandro, Mercedes E., Allard, Patrick, Azamian, Mahshid S., Bacino, Carlos A., Balasubramanyam, Ashok, Barseghyan, Hayk, Batzli, Gabriel F., Beggs, Alan H., Behnam, Babak, Bican, Anna, Bick, David P., Birch, Camille L., Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Briere, Lauren C., Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Chen, Shan, Clark, Gary D., Coakley, Terra R., Cogan, Joy D., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., D’Souza, Precilla, Davids, Mariska, Dayal, Jyoti G., Dell’Angelica, Esteban C., Dhar, Shweta U., Dillon, Ani, Dipple, Katrina M., Donnell-Fink, Laurel A., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Eskin, Ascia, Esteves, Cecilia, Estwick, Tyra, Ferreira, Carlos, Fogel, Brent L., Friedman, Noah D., Gahl, William A., Glanton, Emily, Godfrey, Rena A., Goldstein, David B., Gould, Sarah E., Gourdine, Jean-Philippe F., Groden, Catherine A., Gropman, Andrea L., Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A., Handley, Lori H., Herzog, Matthew R., Holm, Ingrid A., Hom, Jason, Howerton, Ellen M., Huang, Yong, Jacob, Howard J., Jain, Mahim, Jiang, Yong-hui, Johnston, Jean M., Jones, Angela L., Kohane, Isaac S., Krasnewich, Donna M., Krieg, Elizabeth L., Krier, Joel B., Lalani, Seema R., Lau, C. Christopher, Lazar, Jozef, Lee, Brendan H., Lee, Hane, Levy, Shawn E., Lewis, Richard A., Lincoln, Sharyn A., Lipson, Allen, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Markello, Thomas C., Marom, Ronit, Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Might, Matthew, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murphy, Jennifer L., Muzny, Donna M., Nehrebecky, Michele E., Nelson, Stan F., Newberry, J. Scott, Newman, John H., Nicholas, Sarah K., Novacic, Donna, Orange, Jordan S., Pallais, J. Carl, Palmer, Christina G. S., Papp, Jeanette C., Parker, Neil H., Pena, Loren D. M., Phillips, John A., Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Reuter, Chloe M., Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Sampson, Jacinda B., Samson, Susan L., Schoch, Kelly, Schroeder, Molly C., Scott, Daryl A., Sharma, Prashant, Shashi, Vandana, Silverman, Edwin K., Sinsheimer, Janet S., Smith, Kevin S., Spillmann, Rebecca C., Splinter, Kimberly, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sweetser, David A., Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Valivullah, Zaheer M., Vilain, Eric, Vogel, Tiphanie P., Wahl, Colleen E., Walley, Nicole M., Walsh, Chris A., Ward, Patricia A., Waters, Katrina M., Westerfield, Monte, Wise, Anastasia L., Wolfe, Lynne A., Worthey, Elizabeth A., Yamamoto, Shinya, Yang, Yaping, Yu, Guoyun, Zastrow, Diane B., and Zheng, Allison. Thu . "Biallelic Mutations in ATP5F1D , which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder". United States. doi:10.1016/j.ajhg.2018.01.020. https://www.osti.gov/servlets/purl/1423326.
@article{osti_1423326,
title = {Biallelic Mutations in ATP5F1D , which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder},
author = {Oláhová, Monika and Yoon, Wan Hee and Thompson, Kyle and Jangam, Sharayu and Fernandez, Liliana and Davidson, Jean M. and Kyle, Jennifer E. and Grove, Megan E. and Fisk, Dianna G. and Kohler, Jennefer N. and Holmes, Matthew and Dries, Annika M. and Huang, Yong and Zhao, Chunli and Contrepois, Kévin and Zappala, Zachary and Frésard, Laure and Waggott, Daryl and Zink, Erika M. and Kim, Young-Mo and Heyman, Heino M. and Stratton, Kelly G. and Webb-Robertson, Bobbie-Jo M. and Snyder, Michael and Merker, Jason D. and Montgomery, Stephen B. and Fisher, Paul G. and Feichtinger, René G. and Mayr, Johannes A. and Hall, Julie and Barbosa, Ines A. and Simpson, Michael A. and Deshpande, Charu and Waters, Katrina M. and Koeller, David M. and Metz, Thomas O. and Morris, Andrew A. and Schelley, Susan and Cowan, Tina and Friederich, Marisa W. and McFarland, Robert and Van Hove, Johan L. K. and Enns, Gregory M. and Yamamoto, Shinya and Ashley, Euan A. and Wangler, Michael F. and Taylor, Robert W. and Bellen, Hugo J. and Bernstein, Jonathan A. and Wheeler, Matthew T. and Adams, David R. and Alejandro, Mercedes E. and Allard, Patrick and Azamian, Mahshid S. and Bacino, Carlos A. and Balasubramanyam, Ashok and Barseghyan, Hayk and Batzli, Gabriel F. and Beggs, Alan H. and Behnam, Babak and Bican, Anna and Bick, David P. and Birch, Camille L. and Bonner, Devon and Boone, Braden E. and Bostwick, Bret L. and Briere, Lauren C. and Brown, Donna M. and Brush, Matthew and Burke, Elizabeth A. and Burrage, Lindsay C. and Chen, Shan and Clark, Gary D. and Coakley, Terra R. and Cogan, Joy D. and Cooper, Cynthia M. and Cope, Heidi and Craigen, William J. and D’Souza, Precilla and Davids, Mariska and Dayal, Jyoti G. and Dell’Angelica, Esteban C. and Dhar, Shweta U. and Dillon, Ani and Dipple, Katrina M. and Donnell-Fink, Laurel A. and Dorrani, Naghmeh 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 Eskin, Ascia and Esteves, Cecilia and Estwick, Tyra and Ferreira, Carlos and Fogel, Brent L. and Friedman, Noah D. and Gahl, William A. and Glanton, Emily 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 Haendel, Melissa and Hamid, Rizwan and Hanchard, Neil A. and Handley, Lori H. and Herzog, Matthew R. and Holm, Ingrid A. and Hom, Jason and Howerton, Ellen M. and Huang, Yong and Jacob, Howard J. and Jain, Mahim and Jiang, Yong-hui 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 Lazar, Jozef and Lee, Brendan H. and Lee, Hane and Levy, Shawn E. and Lewis, Richard A. and Lincoln, Sharyn A. and Lipson, Allen and Loo, Sandra K. and Loscalzo, Joseph 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 Marom, Ronit and Martínez-Agosto, Julian A. and Marwaha, Shruti and May, Thomas and McConkie-Rosell, Allyn and McCormack, Colleen E. and McCray, Alexa T. and Might, Matthew and Moretti, Paolo M. and Morimoto, Marie 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 Novacic, Donna 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, John A. and Posey, Jennifer E. and Postlethwait, John H. and Potocki, Lorraine 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 Schoch, Kelly and Schroeder, Molly C. and Scott, Daryl A. and Sharma, Prashant and Shashi, Vandana and Silverman, Edwin K. and Sinsheimer, Janet S. and Smith, Kevin S. and Spillmann, Rebecca C. and Splinter, Kimberly and Stoler, Joan M. and Stong, Nicholas and Sullivan, Jennifer A. and Sweetser, David A. and Tifft, Cynthia J. and Toro, Camilo and Tran, Alyssa A. and Urv, Tiina K. and Valivullah, Zaheer M. and Vilain, Eric 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 Westerfield, Monte and Wise, Anastasia L. and Wolfe, Lynne A. and Worthey, Elizabeth A. and Yamamoto, Shinya and Yang, Yaping and Yu, Guoyun and Zastrow, Diane B. and Zheng, Allison},
abstractNote = {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.},
doi = {10.1016/j.ajhg.2018.01.020},
journal = {American Journal of Human Genetics},
number = 3,
volume = 102,
place = {United States},
year = {Thu Feb 22 00:00:00 EST 2018},
month = {Thu Feb 22 00:00:00 EST 2018}
}

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