1. Human Biology and Medicine
  2. Neuroscience
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Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay

  1. Myungjin Kim
  2. Erin Sandford
  3. Damian Gatica
  4. Yu Qiu
  5. Xu Liu
  6. Yumei Zheng
  7. Brenda A Schulman
  8. Jishu Xu
  9. Ian Semple
  10. Seung-Hyun Ro
  11. Boyoung Kim
  12. R Nehir Mavioglu
  13. Aslıhan Tolun
  14. Andras Jipa
  15. Szabolcs Takats
  16. Manuela Karpati
  17. Jun Z Li
  18. Zuhal Yapici
  19. Gabor Juhasz
  20. Jun Hee Lee
  21. Daniel J Klionsky
  22. Margit Burmeister Is a corresponding author
  1. University of Michigan, United States
  2. St Jude Children's Research Hospital, United States
  3. University of Michigan-Ann Arbor, United States
  4. St. Jude Children's Research Hospital, United States
  5. Boğaziçi University, Turkey
  6. Eötvös Loránd University, Hungary
  7. Istanbul University, Turkey
Research Article
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Cite as: eLife 2016;5:e12245 doi: 10.7554/eLife.12245

Abstract

Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.

Article and author information

Author details

  1. Myungjin Kim

    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Erin Sandford

    1. Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Damian Gatica

    1. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yu Qiu

    1. Department of Structural Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xu Liu

    1. Department of Molecular, Cellular, and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yumei Zheng

    1. Department of Structural Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brenda A Schulman

    1. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jishu Xu

    1. Department of Human Genetics, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ian Semple

    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Seung-Hyun Ro

    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Boyoung Kim

    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. R Nehir Mavioglu

    1. Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  13. Aslıhan Tolun

    1. Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  14. Andras Jipa

    1. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  15. Szabolcs Takats

    1. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  16. Manuela Karpati

    1. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  17. Jun Z Li

    1. Department of Human Genetics, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Zuhal Yapici

    1. Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  19. Gabor Juhasz

    1. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  20. Jun Hee Lee

    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Daniel J Klionsky

    1. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Margit Burmeister

    1. Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, United States
    For correspondence
    1. margit@umich.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: Study protocols including written informed consents have been approved by the University of Michigan Institutional Review Board and the Boğaziçi University Institutional Review Board for Research with Human Participants.

Reviewing Editor

  1. Noboru Mizushima, Reviewing Editor, The University of Tokyo, Japan

Publication history

  1. Received: October 11, 2015
  2. Accepted: January 13, 2016
  3. Accepted Manuscript published: January 26, 2016 (version 1)
  4. Version of Record published: March 1, 2016 (version 2)

Copyright

© 2016, Kim et al

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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