title: Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.
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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Sandford
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States.|Life Sciences Institute, University of Michigan, Ann Arbor, United States.
authors.forename: Damian
authors.initials: D
authors.lastname: Gatica
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States.|Life Sciences Institute, University of Michigan, Ann Arbor, United States.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, United States.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, United States.|Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Schulman
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, United States.
authors.forename: Jishu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Ian
authors.initials: I
authors.lastname: Semple
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
authors.forename: R Nehir
authors.initials: RN
authors.lastname: Mavioglu
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
authors.forename: Aslıhan
authors.initials: A
authors.lastname: Tolun
authors.affiliation: Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.|Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Andras
authors.initials: A
authors.lastname: Jipa
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Takats
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Manuela
authors.initials: M
authors.lastname: Karpati
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, United States.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States.
authors.forename: Jun Z
authors.identifier: http://orcid.org/0000-0001-6727-0812
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Neurology, Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Zuhal
authors.initials: Z
authors.lastname: Yapici
authors.affiliation: Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.|Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Gabor
authors.identifier: http://orcid.org/0000-0001-8548-8874
authors.initials: G
authors.lastname: Juhasz
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Jun Hee
authors.identifier: http://orcid.org/0000-0002-2200-6011
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States.|Life Sciences Institute, University of Michigan, Ann Arbor, United States.
authors.forename: Daniel J
authors.identifier: http://orcid.org/0000-0002-7828-8118
authors.initials: DJ
authors.lastname: Klionsky
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, United States.|Department of Human Genetics, University of Michigan, Ann Arbor, United States.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States.|Department of Psychiatry, University of Michigan, Ann Arbor, United States.
authors.forename: Margit
authors.identifier: http://orcid.org/0000-0002-1914-2434
authors.initials: M
authors.lastname: Burmeister
mesh_terms: D000818:Animals; D001259:Ataxia / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D001343:Autophagy; D000071192:Autophagy-Related Protein 12 / Q000235:genetics* / Q000378:metabolism; D000071187:Autophagy-Related Protein 5 / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D004330:Drosophila / Q000235:genetics / Q000502:physiology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D035781:Siblings; D014421:Turkey
chemical_list: C466624:ATG12 protein, human; C502778:ATG5 protein, human; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5
keywords: <i>d. melanogaster</i>; <i>s. cerevisiae</i>; ataxia; autophagy; human; human biology; medicine; neuroscience; next generation sequencing
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