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Published on: August 15, 2019
Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever
Kohji Kato1,2,3, Yasuyoshi Oka4,5, Hideki Muramatsu2
1Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Aichi, Japan.
Insights
Biallelic loss-of-function variants in VPS35L cause 3C/Ritscher-Schinzel-like syndrome. VPS35L is crucial for cellular autophagy and early embryonic development, highlighting the retriever complex
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Cell Biology
Background:
- 3C/Ritscher-Schinzel syndrome is a rare genetic disorder characterized by congenital cranio-cerebello-cardiac dysplasia.
- Known causative genes CCDC22 and WASHC5 are involved in endosomal protein recycling via the retromer/retriever complex.
- The study investigates siblings with a similar syndrome to identify novel genetic underpinnings.
Purpose of the Study:
- To identify the specific gene abnormality responsible for a 3C/Ritscher-Schinzel-like syndrome in affected siblings.
- To elucidate the function of the identified gene and the pathophysiological significance of the variants.
- To understand the role of the retriever complex in embryonic development and autophagy.
Main Methods:
- Whole exome sequencing was employed to detect pathogenic genetic variants.
- Cellular assays were conducted to analyze gene function and variant impact.
- Knockout mouse models were generated to study in vivo gene function and developmental roles.
Main Results:
- Compound heterozygous pathogenic variants in the VPS35L gene were identified.
- VPS35L variants led to loss of function, impaired retriever complex formation, and decreased autophagic activity in cells.
- VPS35L knockout mice exhibited embryonic lethality during early development (E7.5-E10.5).
Conclusions:
- Biallelic loss-of-function variants in VPS35L are implicated as the cause of 3C/Ritscher-Schinzel-like syndrome.
- VPS35L is essential for maintaining autophagic function and critical for early embryonic development.
- This study reveals a significant role for the retriever complex in fetal development.
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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