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

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 KatoTatsuhiko Tsunoda, Hirotomo Saitsu, Yonehiro Kanemura, Mami Yamasaki, Kenjiro Kosaki, Naomichi Matsumoto, Tamotsu Yoshimori, Shinji Saitoh

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number3552
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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Lysosomes
Clustered Regularly Interspaced Short Palindromic Repeats
Fibroblasts
Agenesis of Corpus Callosum
Hypopigmentation
Skin
Mutation
Initiator Codon
Sequence Deletion
Autophagy
HeLa Cells
Small Interfering RNA
Dissection
Exons
Autophagosomes
Neurodevelopmental Disorders
Absent corpus callosum cataract immunodeficiency
Biopsy
Muscles
Brain

ASJC Scopus subject areas

  • General

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Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. / Hori, Ikumi; Otomo, Takanobu; Nakashima, Mitsuko; Miya, Fuyuki; Negishi, Yutaka; Shiraishi, Hideaki; Nonoda, Yutaka; Magara, Shinichi; Tohyama, Jun; Okamoto, Nobuhiko; Kumagai, Takeshi; Shimoda, Konomi; Yukitake, Yoshiya; Kajikawa, Daigo; Morio, Tomohiro; Hattori, Ayako; Nakagawa, Motoo; Ando, Naoki; Nishino, Ichizo; Kato, Mitsuhiro; Tsunoda, Tatsuhiko; Saitsu, Hirotomo; Kanemura, Yonehiro; Yamasaki, Mami; Kosaki, Kenjiro; Matsumoto, Naomichi; Yoshimori, Tamotsu; Saitoh, Shinji.

In: Scientific Reports, Vol. 7, No. 1, 3552, 01.12.2017.

Research output: Contribution to journalArticle

Hori, I, Otomo, T, Nakashima, M, Miya, F, Negishi, Y, Shiraishi, H, Nonoda, Y, Magara, S, Tohyama, J, Okamoto, N, Kumagai, T, Shimoda, K, Yukitake, Y, Kajikawa, D, Morio, T, Hattori, A, Nakagawa, M, Ando, N, Nishino, I, Kato, M, Tsunoda, T, Saitsu, H, Kanemura, Y, Yamasaki, M, Kosaki, K, Matsumoto, N, Yoshimori, T & Saitoh, S 2017, 'Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement', Scientific Reports, vol. 7, no. 1, 3552. https://doi.org/10.1038/s41598-017-02840-8
Hori, Ikumi ; Otomo, Takanobu ; Nakashima, Mitsuko ; Miya, Fuyuki ; Negishi, Yutaka ; Shiraishi, Hideaki ; Nonoda, Yutaka ; Magara, Shinichi ; Tohyama, Jun ; Okamoto, Nobuhiko ; Kumagai, Takeshi ; Shimoda, Konomi ; Yukitake, Yoshiya ; Kajikawa, Daigo ; Morio, Tomohiro ; Hattori, Ayako ; Nakagawa, Motoo ; Ando, Naoki ; Nishino, Ichizo ; Kato, Mitsuhiro ; Tsunoda, Tatsuhiko ; Saitsu, Hirotomo ; Kanemura, Yonehiro ; Yamasaki, Mami ; Kosaki, Kenjiro ; Matsumoto, Naomichi ; Yoshimori, Tamotsu ; Saitoh, Shinji. / Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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AU - Hori, Ikumi

AU - Otomo, Takanobu

AU - Nakashima, Mitsuko

AU - Miya, Fuyuki

AU - Negishi, Yutaka

AU - Shiraishi, Hideaki

AU - Nonoda, Yutaka

AU - Magara, Shinichi

AU - Tohyama, Jun

AU - Okamoto, Nobuhiko

AU - Kumagai, Takeshi

AU - Shimoda, Konomi

AU - Yukitake, Yoshiya

AU - Kajikawa, Daigo

AU - Morio, Tomohiro

AU - Hattori, Ayako

AU - Nakagawa, Motoo

AU - Ando, Naoki

AU - Nishino, Ichizo

AU - Kato, Mitsuhiro

AU - Tsunoda, Tatsuhiko

AU - Saitsu, Hirotomo

AU - Kanemura, Yonehiro

AU - Yamasaki, Mami

AU - Kosaki, Kenjiro

AU - Matsumoto, Naomichi

AU - Yoshimori, Tamotsu

AU - Saitoh, Shinji

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