title: 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). 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.
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. hsaitsu@yokohama-cu.ac.jp
authors: Hirotomo
authors: H
authors: Saitsu
authors: Taki
authors: T
authors: Nishimura
authors: Kazuhiro
authors: K
authors: Muramatsu
authors: Hirofumi
authors: H
authors: Kodera
authors: Satoko
authors: S
authors: Kumada
authors: Kenji
authors: K
authors: Sugai
authors: Emi
authors: E
authors: Kasai-Yoshida
authors: Noriko
authors: N
authors: Sawaura
authors: Hiroya
authors: H
authors: Nishida
authors: Ai
authors: A
authors: Hoshino
authors: Fukiko
authors: F
authors: Ryujin
authors: Seiichiro
authors: S
authors: Yoshioka
authors: Kiyomi
authors: K
authors: Nishiyama
authors: Yukiko
authors: Y
authors: Kondo
authors: Yoshinori
authors: Y
authors: Tsurusaki
authors: Mitsuko
authors: M
authors: Nakashima
authors: Noriko
authors: N
authors: Miyake
authors: Hirokazu
authors: H
authors: Arakawa
authors: Mitsuhiro
authors: M
authors: Kato
authors: Noboru
authors: N
authors: Mizushima
authors: Naomichi
authors: N
authors: Matsumoto
mesh_terms: D000328:Adult; D001343:Autophagy; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D059472:Exome / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology*; D007501:Iron / Q000378:metabolism; D065768:Lennox Gastaut Syndrome; D008279:Magnetic Resonance Imaging; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000209:etiology*; D010641:Phenotype; D013036:Spasms, Infantile / Q000209:etiology*
chemical_list: D002352:Carrier Proteins; C578284:WDR45 protein, human; D007501:Iron