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

Autor: 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
Rok vydání: 2022
Předmět:
Zdroj: Journal of Medical Genetics. 60:359-367
ISSN: 1468-6244
0022-2593
Popis: PurposeThe Retriever subunitVPS35Lis the third responsible gene for Ritscher-Schinzel syndrome (RSS) afterWASHC5andCCDC22. 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.MethodsWe report three new patients with biallelicVPS35Lvariants. 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 withCCDC22andWASHC5variants. 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.ConclusionVPS35L-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.
Databáze: OpenAIRE
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