Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay

Myungjin Kim, Erin Sandford, Damian Gatica, Yu Qiu, Xu Liu, Yumei Zheng, Brenda A. Schulman, Jishu Xu, Ian Semple, Seung Hyun Ro, Boyoung Kim, R. Nehir Mavioglu, Aslihan Tolun, Andras Jipa, Szabolcs Takats, Manuela Karpati, Jun Z. Li, Zuhal Yapici, G. Juhász, Jun Hee LeeDaniel J. Klionsky, Margit Burmeister

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Autoph agy 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.

Original languageEnglish
Article numbere12245
JournaleLife
Volume5
Issue numberJANUARY2016
DOIs
Publication statusPublished - Jan 26 2016

Fingerprint

Autophagy
Ataxia
Health
Defects
Mutation
Yeast
Diptera
Genes
Fluxes
Amino Acids
Movement Disorders
Missense Mutation
Proteins
Intellectual Disability
Neurodegenerative Diseases
Siblings
Homeostasis
Yeasts

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Kim, M., Sandford, E., Gatica, D., Qiu, Y., Liu, X., Zheng, Y., ... Burmeister, M. (2016). Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. eLife, 5(JANUARY2016), [e12245]. https://doi.org/10.7554/eLife.12245.001

Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. / Kim, Myungjin; Sandford, Erin; Gatica, Damian; Qiu, Yu; Liu, Xu; Zheng, Yumei; Schulman, Brenda A.; Xu, Jishu; Semple, Ian; Ro, Seung Hyun; Kim, Boyoung; Mavioglu, R. Nehir; Tolun, Aslihan; Jipa, Andras; Takats, Szabolcs; Karpati, Manuela; Li, Jun Z.; Yapici, Zuhal; Juhász, G.; Lee, Jun Hee; Klionsky, Daniel J.; Burmeister, Margit.

In: eLife, Vol. 5, No. JANUARY2016, e12245, 26.01.2016.

Research output: Contribution to journalArticle

Kim, M, Sandford, E, Gatica, D, Qiu, Y, Liu, X, Zheng, Y, Schulman, BA, Xu, J, Semple, I, Ro, SH, Kim, B, Mavioglu, RN, Tolun, A, Jipa, A, Takats, S, Karpati, M, Li, JZ, Yapici, Z, Juhász, G, Lee, JH, Klionsky, DJ & Burmeister, M 2016, 'Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay', eLife, vol. 5, no. JANUARY2016, e12245. https://doi.org/10.7554/eLife.12245.001
Kim M, Sandford E, Gatica D, Qiu Y, Liu X, Zheng Y et al. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. eLife. 2016 Jan 26;5(JANUARY2016). e12245. https://doi.org/10.7554/eLife.12245.001
Kim, Myungjin ; Sandford, Erin ; Gatica, Damian ; Qiu, Yu ; Liu, Xu ; Zheng, Yumei ; Schulman, Brenda A. ; Xu, Jishu ; Semple, Ian ; Ro, Seung Hyun ; Kim, Boyoung ; Mavioglu, R. Nehir ; Tolun, Aslihan ; Jipa, Andras ; Takats, Szabolcs ; Karpati, Manuela ; Li, Jun Z. ; Yapici, Zuhal ; Juhász, G. ; Lee, Jun Hee ; Klionsky, Daniel J. ; Burmeister, Margit. / Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. In: eLife. 2016 ; Vol. 5, No. JANUARY2016.
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