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De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood

Nature Genetics volume 45, pages 445–449 (2013)Cite this article

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Abstract

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA)1,2,3. By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45 encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy4,5. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.

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Figure 1: Heterozygous WDR45 mutations in individuals with SENDA.
Figure 2: Brain MRIs at 3.0 T and 1.5 T.
Figure 3: Defective autophagy in LCLs derived from subjects with SENDA.

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References

  1. Gregory, A., Polster, B.J. & Hayflick, S.J. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J. Med. Genet. 46, 73–80 (2009).

    Article  CAS  Google Scholar 

  2. Kruer, M.C. et al. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am. J. Neuroradiol. 33, 407–414 (2012).

    Article  CAS  Google Scholar 

  3. Schneider, S.A. & Bhatia, K.P. Syndromes of neurodegeneration with brain iron accumulation. Semin. Pediatr. Neurol. 19, 57–66 (2012).

    Article  Google Scholar 

  4. Polson, H.E. et al. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6, 506–522 (2010).

    Article  CAS  Google Scholar 

  5. Lu, Q. et al. The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. Dev. Cell 21, 343–357 (2011).

    Article  CAS  Google Scholar 

  6. Gregory, A. & Hayflick, S.J. Genetics of neurodegeneration with brain iron accumulation. Curr. Neurol. Neurosci. Rep. 11, 254–261 (2011).

    Article  CAS  Google Scholar 

  7. Kimura, Y. et al. MRI, MR spectroscopy, and diffusion tensor imaging findings in patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). Brain Dev. published online; doi:10.1016/j.braindev.2012.07.008 (11 August 2012).

  8. Kasai-Yoshida, E. et al. First video report of static encephalopathy of childhood with neurodegeneration in adulthood. Mov. Disord. published online; doi:10.1002/mds.25158 (6 February 2013).

  9. Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).

    Article  CAS  Google Scholar 

  10. Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467 (2009).

    Article  CAS  Google Scholar 

  11. Xie, Z. & Klionsky, D.J. Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9, 1102–1109 (2007).

    Article  CAS  Google Scholar 

  12. Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011).

    Article  CAS  Google Scholar 

  13. Baskaran, S., Ragusa, M.J., Boura, E. & Hurley, J.H. Two-site recognition of phosphatidylinositol 3-phosphate by PROPPINs in autophagy. Mol. Cell 47, 339–348 (2012).

    Article  CAS  Google Scholar 

  14. Krick, R. et al. Structural and functional characterization of the two phosphoinositide binding sites of PROPPINs, a β-propeller protein family. Proc. Natl. Acad. Sci. USA 109, E2042–E2049 (2012).

    Article  CAS  Google Scholar 

  15. Watanabe, Y. et al. Structure-based analyses reveal distinct binding sites for Atg2 and phosphoinositides in Atg18. J. Biol. Chem. 287, 31681–31690 (2012).

    Article  CAS  Google Scholar 

  16. Suzuki, K., Kubota, Y., Sekito, T. & Ohsumi, Y. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12, 209–218 (2007).

    Article  CAS  Google Scholar 

  17. Velikkakath, A.K., Nishimura, T., Oita, E., Ishihara, N. & Mizushima, N. Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol. Biol. Cell 23, 896–909 (2012).

    Article  CAS  Google Scholar 

  18. Mizushima, N., Yoshimori, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313–326 (2010).

    Article  CAS  Google Scholar 

  19. Itakura, E., Kishi-Itakura, C., Koyama-Honda, I. & Mizushima, N. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J. Cell Sci. 125, 1488–1499 (2012).

    Article  CAS  Google Scholar 

  20. Orsi, A. et al. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol. Biol. Cell 23, 1860–1873 (2012).

    Article  CAS  Google Scholar 

  21. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    Article  CAS  Google Scholar 

  22. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    Article  CAS  Google Scholar 

  23. Menzies, F.M., Moreau, K. & Rubinsztein, D.C. Protein misfolding disorders and macroautophagy. Curr. Opin. Cell Biol. 23, 190–197 (2011).

    Article  CAS  Google Scholar 

  24. Valente, E.M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    Article  CAS  Google Scholar 

  25. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    Article  CAS  Google Scholar 

  26. Youle, R.J. & van der Bliek, A.M. Mitochondrial fission, fusion, and stress. Science 337, 1062–1065 (2012).

    Article  CAS  Google Scholar 

  27. Youle, R.J. & Narendra, D.P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 (2011).

    Article  CAS  Google Scholar 

  28. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    Article  CAS  Google Scholar 

  29. Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268 (2008).

    Article  CAS  Google Scholar 

  30. Saitoh, T. et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl. Acad. Sci. USA 106, 20842–20846 (2009).

    Article  CAS  Google Scholar 

  31. Sou, Y.S. et al. The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol. Biol. Cell 19, 4762–4775 (2008).

    Article  CAS  Google Scholar 

  32. Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    Article  CAS  Google Scholar 

  33. Haack, T.B. et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am. J. Hum. Genet. 91, 1144–1149 (2012).

    Article  CAS  Google Scholar 

  34. Proikas-Cezanne, T. et al. WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23, 9314–9325 (2004).

    Article  CAS  Google Scholar 

  35. DePristo, M.A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).

    Article  CAS  Google Scholar 

  36. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  Google Scholar 

  37. Saitsu, H. et al. STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. Epilepsia 51, 2397–2405 (2010).

    Article  CAS  Google Scholar 

  38. Kondo, Y. et al. A family of oculofaciocardiodental syndrome (OFCD) with a novel BCOR mutation and genomic rearrangements involving NHS. J. Hum. Genet. 57, 197–201 (2012).

    Article  CAS  Google Scholar 

  39. Allen, R.C., Zoghbi, H.Y., Moseley, A.B., Rosenblatt, H.M. & Belmont, J.W. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet. 51, 1229–1239 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Carrel, L. & Willard, H.F. An assay for X inactivation based on differential methylation at the fragile X locus, FMR1. Am. J. Med. Genet. 64, 27–30 (1996).

    Article  CAS  Google Scholar 

  41. Hosokawa, N., Hara, Y. & Mizushima, N. Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett. 580, 2623–2629 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank the individuals with SENDA and their families for their participation in this study. We thank M. Shiina and K. Ogata for their helpful comments on the protein structure. This work was supported by research grants from the Ministry of Health, Labour and Welfare (H.S., N. Miyake and N. Matsumoto), the Japan Science and Technology Agency (N. Matsumoto) and the Strategic Research Program for Brain Sciences (N. Matsumoto) and by a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (N. Matsumoto), a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (N. Matsumoto), a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science (H.S. and N. Miyake), the Funding Program for Next-Generation World-Leading Researchers (N. Mizushima) and a grant from the Takeda Science Foundation (N. Miyake, N. Mizushima and N. Matsumoto).

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Author notes

  1. Hirotomo Saitsu, Taki Nishimura and Kazuhiro Muramatsu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan

    Hirotomo Saitsu, Hirofumi Kodera, Kiyomi Nishiyama, Yukiko Kondo, Yoshinori Tsurusaki, Mitsuko Nakashima, Noriko Miyake & Naomichi Matsumoto

  2. Department of Physiology and Cell Biology, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Taki Nishimura & Noboru Mizushima

  3. Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Taki Nishimura & Noboru Mizushima

  4. Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan

    Kazuhiro Muramatsu, Noriko Sawaura & Hirokazu Arakawa

  5. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Satoko Kumada & Emi Kasai-Yoshida

  6. Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan

    Kenji Sugai

  7. Department of Pediatrics, National Rehabilitation Center for Children with Disabilities, Tokyo, Japan

    Hiroya Nishida & Ai Hoshino

  8. Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan

    Fukiko Ryujin & Seiichiro Yoshioka

  9. Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan

    Mitsuhiro Kato

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  1. Hirotomo Saitsu
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Contributions

H.S., N. Mizushima and N. Matsumoto designed and directed the study. H.S., T.N., K.M., N. Mizushima and N. Matsumoto wrote the manuscript. K.M., S.K., K.S., E.K.-Y., N.S., H.N., A.H., F.R., S.Y., H.A. and M.K. collected samples and provided the subjects' clinical information. H.S., H.K., K.N., Y.T., M.N. and N. Miyake performed exome sequencing and Sanger sequencing. H.S. and K.N. performed the RNA analysis. Y.K. performed the X-inactivation analysis. T.N. and N. Mizushima analyzed protein expression and autophagic activity.

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Correspondence to Hirotomo Saitsu, Noboru Mizushima or Naomichi Matsumoto.

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Saitsu, H., Nishimura, T., Muramatsu, K. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 45, 445–449 (2013). https://doi.org/10.1038/ng.2562

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