Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-06-14

AUTHORS

Ikumi Hori, Takanobu Otomo, Mitsuko Nakashima, Fuyuki Miya, Yutaka Negishi, Hideaki Shiraishi, Yutaka Nonoda, Shinichi Magara, Jun Tohyama, Nobuhiko Okamoto, Takeshi Kumagai, Konomi Shimoda, Yoshiya Yukitake, Daigo Kajikawa, Tomohiro Morio, Ayako Hattori, Motoo Nakagawa, Naoki Ando, Ichizo Nishino, Mitsuhiro Kato, Tatsuhiko Tsunoda, Hirotomo Saitsu, Yonehiro Kanemura, Mami Yamasaki, Kenjiro Kosaki, Naomichi Matsumoto, Tamotsu Yoshimori, Shinji Saitoh

ABSTRACT

Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion. More... »

PAGES

3552

Journal

TITLE

Scientific Reports

ISSUE

1

VOLUME

7

Author Affiliations

  • Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601 Japan
  • Research Center for Autophagy, Osaka University Graduate School of Medicine, Osaka, 565-0871 Japan
  • Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004 Japan
  • Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan
  • Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638 Japan
  • Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, 252-0373 Japan
  • Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, 950-2085 Japan
  • Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, 594-1101 Japan
  • Department of Pediatrics, Wakayama Medical University, Wakayama, 641-8509 Japan
  • Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655 Japan
  • Department of Neonatology, Ibaraki Children’s Hospital, Mito, 311-4145 Japan
  • Department of Child Health, Faculty of Medicine, Tsukuba University, Tsukuba, 305-8576 Japan
  • Department of Pediatrics, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8519 Japan
  • Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601 Japan
  • Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8551 Japan
  • Department of Pediatrics, Showa University School of Medicine, Tokyo, 142-8666 Japan
  • Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, 431-3192 Japan
  • Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, 540-0006 Japan
  • Department of Neurosurgery, Takatsuki General Hospital, Osaka, 569-1192 Japan
  • Center for Medical Genetics, Keio University School of Medicine, Tokyo, 160-8582 Japan
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41598-017-02840-8

    DOI

    http://dx.doi.org/10.1038/s41598-017-02840-8

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1085943256

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28615637


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