Takanobu Otomo    Department   Kawasaki Medical School  Kawasaki Medical School, Department of Molecular and Genetic Medicine,    Position   Professor
Article types	原著
Language	English
Peer review	Peer reviewed
Title	Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.
Journal	Formal name：Journal of medical genetics Abbreviation：J Med Genet ISSN code：14686244/00222593
Domestic / Foregin	Foregin
Volume, Issue, Page	57(4),pp.245-253
Author and coauthor	Kato Kohji, Oka Yasuyoshi, Muramatsu Hideki, Vasilev Filipp F, Otomo Takanobu, Oishi Hisashi, Kawano Yoshihiko, Kidokoro Hiroyuki, Nakazawa Yuka, Ogi Tomoo, Takahashi Yoshiyuki, Saitoh Shinji
Publication date	2020/04
Summary	BACKGROUND:3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where CCDC22 and WASHC5 are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation.METHODS:Exome sequencing was performed to identify pathogenic variants. Cellular biological analyses and generation of knockout mice were carried out to elucidate the gene function and pathophysiological significance of the identified variants.RESULTS:We identified compound heterozygous pathogenic variants (c.1097dup; p.Cys366Trpfs*28 and c.2755G>A; p.Ala919Thr) in the VPS35L gene, which encodes a core protein of the retriever complex. The identified missense variant lacked the ability to form the retriever complex, and the frameshift variant induced non-sense-mediated mRNA decay, thereby confirming biallelic loss of function of VPS35L. In addition, VPS35L knockout cells showed decreased autophagic function in nutrient-rich and starvation conditions, as well as following treatment with Torin 1. We also generated Vps35l-/- mice and demonstrated that they were embryonic lethal at an early stage, between E7.5 and E10.5.CONCLUSIONS:Our results suggest that biallelic loss-of-function variants in VPS35L underlies 3C/Ritscher-Schinzel-like syndrome. Furthermore, VPS35L is necessary for autophagic function and essential for early embryonic development. The data presented here provide a new insight into the critical role of the retriever complex in fetal development.
DOI	10.1136/jmedgenet-2019-106213
PMID	31712251