| Autor: |
Shiomi Otsuji, Yosuke Nishio, Maki Tsujita, Marlene Rio, Huber, Céline, Antón-Plágaro, Carlos, Seiji Mizuno, Yoshihiko Kawano, Satoko Miyatake, Simon, Marleen, van Binsbergen, Ellen, van Jaarsveld, Richard H., Naomichi Matsumoto, Cormier-Daire, Valerie, Cullen, Peter J., Shinji Saitoh, Kohji Kato |
| Zdroj: |
Journal of Medical Genetics; Apr2023, Vol. 60 Issue 4, p359-367, 14p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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