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RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation causing a distinct Mendelian Disorder

By Franziska PAUL, Calista Ng, Shahriar Nafissi, Yalda Nilipoor, Ali Reza Tavasoli, Umar Bin Mohamad Sahari, Carine Bonnard, Pui-Mun Wong, Nasrinsadat Nabavizadeh, Mehrdad A. Estiar, Charles B Majoie, Hane Lee, Stanley F. Nelson, Ziv Gan-Or, Guy A. Rouleau, Paul P Van Veldhoven, Rami Massie, Raoul C Hennekam, Ariana Kariminejad, Bruno REVERSADE

Posted 05 Oct 2021
medRxiv DOI: 10.1101/2021.10.03.21264281

Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively-acting germline alleles p.Arg180Gly and p.Gly183Arg which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate PI3P and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts exhibit accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.

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