Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome

Shiomi Otsuji, Yosuke Nishio, Maki Tsujita, Marlene Rio, Céline Huber, Carlos Antón-Plágaro, Seiji Mizuno, Yoshihiko Kawano, Satoko Miyatake, Marleen Simon, Ellen van Binsbergen, Richard H van Jaarsveld, Naomichi Matsumoto, Valerie Cormier-Daire, Peter J Cullen, Shinji Saitoh, Kohji Kato*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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PURPOSE: The Retriever subunit VPS35L is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after WASHC5 and CCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS.

METHODS: We report three new patients with biallelic VPS35L variants. Biochemical and cellular analyses were performed to elucidate disease aetiology.

RESULTS: In addition to typical features of RSS, we confirmed hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia as novel complications of VPS35L-associated RSS. The latter two complications as well as proteinuria have not been reported in patients with CCDC22 and WASHC5 variants. One patient showed a severe phenotype and the other two were milder. Cells established from patients with the milder phenotypes showed relatively higher VPS35L protein expression. Cellular analysis found VPS35L ablation decreased the cell surface level of lipoprotein receptor-related protein 1 and low-density lipoprotein receptor, resulting in reduced low-density lipoprotein cellular uptake.

CONCLUSION: VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia. These findings provide new insight into the essential and distinctive role of Retriever in human development.

Original languageEnglish
Article number108602
Pages (from-to)359-367
Number of pages9
JournalJournal of Medical Genetics
Issue number4
Early online date16 Sept 2022
Publication statusPublished - 1 Apr 2023


  • Medical
  • genetics
  • medical


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