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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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).

Author information

Author notes

    • Hirotomo Saitsu
    • , Taki Nishimura
    •  & Kazuhiro Muramatsu

    These authors contributed equally to this work.

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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hirotomo Saitsu or Noboru Mizushima or Naomichi Matsumoto.

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DOI

https://doi.org/10.1038/ng.2562