Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex

Kohji Kato, Yasuyoshi Oka, Hideki Muramatsu, Filipp F. Vasilev, Takanobu Otomo, Hisashi Oishi, Yoshihiko Kawano, Hiroyuki Kidokoro, Yuka Nakazawa, Tomoo Ogi, Yoshiyuki Takahashi, Shinji Saitoh

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalJournal of medical genetics
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Genes
Chondrodysplasia Punctata
Coloboma
Microphthalmos
Exome
RNA Stability
Recycling
Fetal Development
Starvation
Knockout Mice
Embryonic Development
Virulence
Membrane Proteins
3C syndrome
Food
Proteins
torin

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex. / 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.

In: Journal of medical genetics, 01.01.2019.

Research output: Contribution to journalArticle

Kato, K, Oka, Y, Muramatsu, H, Vasilev, FF, Otomo, T, Oishi, H, Kawano, Y, Kidokoro, H, Nakazawa, Y, Ogi, T, Takahashi, Y & Saitoh, S 2019, 'Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex', Journal of medical genetics. https://doi.org/10.1136/jmedgenet-2019-106213
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. / Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex. In: Journal of medical genetics. 2019.
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abstract = "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.",
author = "Kohji Kato and Yasuyoshi Oka and Hideki Muramatsu and Vasilev, {Filipp F.} and Takanobu Otomo and Hisashi Oishi and Yoshihiko Kawano and Hiroyuki Kidokoro and Yuka Nakazawa and Tomoo Ogi and Yoshiyuki Takahashi and Shinji Saitoh",
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T1 - Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex

AU - Kato, Kohji

AU - Oka, Yasuyoshi

AU - Muramatsu, Hideki

AU - Vasilev, Filipp F.

AU - Otomo, Takanobu

AU - Oishi, Hisashi

AU - Kawano, Yoshihiko

AU - Kidokoro, Hiroyuki

AU - Nakazawa, Yuka

AU - Ogi, Tomoo

AU - Takahashi, Yoshiyuki

AU - Saitoh, Shinji

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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