{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:39:07Z","timestamp":1790617147959,"version":"4.1.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,14]],"date-time":"2017-06-14T00:00:00Z","timestamp":1497398400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,14]],"date-time":"2017-06-14T00:00:00Z","timestamp":1497398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>EPG5<\/jats:italic>, 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 <jats:italic>EPG5<\/jats:italic>. 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 <jats:italic>EPG5<\/jats:italic>, siRNA based <jats:italic>EPG5<\/jats:italic> knock-down, and CRISPR\/Cas9 mediated <jats:italic>EPG5<\/jats:italic> knock-out HeLa cells were generated. <jats:italic>EPG5<\/jats:italic>-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 <jats:italic>EPG5<\/jats:italic> depleted cells, suggesting that <jats:italic>EPG5<\/jats:italic> function is limited to the regulation of autophagosome-lysosome fusion.<\/jats:p>","DOI":"10.1038\/s41598-017-02840-8","type":"journal-article","created":{"date-parts":[[2017,6,8]],"date-time":"2017-06-08T15:18:02Z","timestamp":1496935082000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement"],"prefix":"10.1038","volume":"7","author":[{"given":"Ikumi","family":"Hori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanobu","family":"Otomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuko","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuyuki","family":"Miya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Negishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Shiraishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Nonoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Magara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tohyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kumagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konomi","family":"Shimoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiya","family":"Yukitake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daigo","family":"Kajikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Morio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoo","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Ando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9452-112X","authenticated-orcid":false,"given":"Ichizo","family":"Nishino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiro","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuhiko","family":"Tsunoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0723-0960","authenticated-orcid":false,"given":"Hirotomo","family":"Saitsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonehiro","family":"Kanemura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mami","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenjiro","family":"Kosaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamotsu","family":"Yoshimori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6911-3351","authenticated-orcid":false,"given":"Shinji","family":"Saitoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,14]]},"reference":[{"key":"2840_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/ajmg.1320290102","volume":"29","author":"C Dionisi Vici","year":"1988","unstructured":"Dionisi Vici, C. et al. Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am. J. Med. Genet. \n                           29, 1\u20138 (1988).","journal-title":"Am. J. Med. Genet."},{"key":"2840_CR2","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1002\/(SICI)1096-8628(19990827)85:5<479::AID-AJMG9>3.0.CO;2-D","volume":"85","author":"M del Campo","year":"1999","unstructured":"del Campo, M. et al. Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance. Am. J. Med. Genet. \n                           85, 479\u2013485 (1999).","journal-title":"Am. J. Med. Genet."},{"key":"2840_CR3","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/ajmg.10298","volume":"109","author":"T Chiyonobu","year":"2002","unstructured":"Chiyonobu, T. et al. Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections. 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Vici syndrome: a rare autosomal recessive syndrome with brain anomalies, cardiomyopathy, and severe intellectual disability. Case Rep. Genet. \n                           2011, 421582 (2011).","journal-title":"Case Rep. Genet."},{"key":"2840_CR9","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1002\/ajmg.a.34244","volume":"158","author":"A Finocchi","year":"2012","unstructured":"Finocchi, A. et al. Immunodeficiency in Vici syndrome: a heterogeneous phenotype. Am. J. Med. Genet. A \n                           158, 434\u2013439 (2012).","journal-title":"Am. J. Med. Genet. A"},{"key":"2840_CR10","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.pediatrneurol.2012.07.007","volume":"47","author":"M Ozkale","year":"2012","unstructured":"Ozkale, M., Erol, I., Gumus, A., Ozkale, Y. & Alehan, F. Vici syndrome associated with sensorineural hearing loss and laryngomalacia. Pediatr. 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