2. Academic Validation
  3. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood

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

  • Nat Genet. 2013 Apr;45(4):445-9, 449e1. doi: 10.1038/ng.2562.
Hirotomo Saitsu 1,  Taki Nishimura,  Kazuhiro Muramatsu,  Hirofumi Kodera,  Satoko Kumada,  Kenji Sugai,  Emi Kasai-Yoshida,  Noriko Sawaura,  Hiroya Nishida,  Ai Hoshino,  Fukiko Ryujin,  Seiichiro Yoshioka,  Kiyomi Nishiyama,  Yukiko Kondo,  Yoshinori Tsurusaki,  Mitsuko Nakashima,  Noriko Miyake,  Hirokazu Arakawa,  Mitsuhiro Kato,  Noboru Mizushima,  Naomichi Matsumoto
Affiliations

Affiliation

  • 1 Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. hsaitsu@yokohama-cu.ac.jp
PMID: 23435086 DOI: 10.1038/ng.2562
Abstract

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). 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 Autophagy. 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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