دورية
Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome
| العنوان: | Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome |
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| المؤلفون: | Otsuji, Shiomi, Nishio, Yosuke, Tsujita, Maki, Rio, Marlene, Huber, Céline, Antón-Plágaro, Carlos, Mizuno, Seiji, Kawano, Yoshihiko, Miyatake, Satoko, Simon, Marleen, van Binsbergen, Ellen, van Jaarsveld, Richard H, Matsumoto, Naomichi, Cormier-Daire, Valerie, J.Cullen, Peter, Saitoh, Shinji, Kato, Kohji |
| المصدر: | Journal of Medical Genetics (JMG); 2023, Vol. 60 Issue: 4 p359-367, 9p |
| مستخلص: | PurposeThe Retriever subunit VPS35Lis the third responsible gene for Ritscher-Schinzel syndrome (RSS) after WASHC5and 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.MethodsWe report three new patients with biallelic VPS35Lvariants. 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 CCDC22and WASHC5variants. 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. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 00222593 14686244 |
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| DOI: | 10.1136/jmg-2022-108602 |