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

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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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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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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