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

Autor:	Paul F; Laboratory of Human Genetics & Therapeutics, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore., Ng C; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore., Mohamad Sahari UB; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore., Nafissi S; Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran., Nilipoor Y; Pediatric Pathology Research Centre, Research Institute for Children Health, Shahid Beheshti Medical University, Tehran, Iran., Tavasoli AR; Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Tehran University Of Medical Sciences, Tehran, Iran., Bonnard C; Model Development, A*STAR Skin Research Labs (ASRL), Singapore., Wong PM; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore., Nabavizadeh N; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore.; Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.; Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey., Altunoğlu U; Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey., Estiar MA; Department of Human Genetics, McGill University, Montréal, Québec, Canada.; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Québec, Canada., Majoie CB; Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands., Lee H; 3billion Inc., Seoul, South Korea.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Nelson SF; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Gan-Or Z; Department of Human Genetics, McGill University, Montréal, Québec, Canada.; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada., Rouleau GA; Department of Human Genetics, McGill University, Montréal, Québec, Canada.; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada., Van Veldhoven PP; Laboratory of Lipid Biochemistry and Protein Interactions (LIPIT), Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Massie R; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada., Hennekam RC; Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands., Kariminejad A; Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran., Reversade B; Laboratory of Human Genetics & Therapeutics, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore.; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore.; Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2022 Oct 28; Vol. 31 (21), pp. 3729-3740.
DOI:	10.1093/hmg/ddac120
Abstrakt:	Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, 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 phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show 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. (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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