Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder

Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder Publisher Pubmed

Paul F¹ ; Ng C² ; Mohamad Sahari UB² ; Nafissi S³ ; Nilipoor Y⁴ ; Tavasoli AR⁵ ; Bonnard C⁶ ; Wong PM² ; Nabavizadeh N^{2, 7, 8} ; Altunoglu U⁸ ; Estiar MA^{9, 10} ; Majoie CB¹¹ ; Lee H^{12, 13, 14} ; Nelson SF^{13, 14} Show All Authors

Paul F¹
Ng C²
Mohamad Sahari UB²
Nafissi S³
Nilipoor Y⁴
Tavasoli AR⁵
Bonnard C⁶
Wong PM²
Nabavizadeh N^{2, 7, 8}
Altunoglu U⁸
Estiar MA^{9, 10}
Majoie CB¹¹
Lee H^{12, 13, 14}
Nelson SF^{13, 14}
Ganor Z^{9, 10, 15}
Rouleau GA^{9, 10, 15}
Van Veldhoven PP¹⁶
Massie R^{10, 15}
Hennekam RC¹⁷
Kariminejad A¹⁸
Reversade B^{1, 2, 8}

Show Affiliations

1. Laboratory of Human Genetics & Therapeutics, Institute of Molecular and Cell Biology (IMCB), ASTAR, Singapore
2. Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), ASTAR, Singapore
3. Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
4. Pediatric Pathology Research Centre, Research Institute for Children Health, Shahid Beheshti Medical University, Tehran, Iran
5. Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
6. Model Development, ASTAR Skin Research Labs (ASRL), Singapore
7. Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
8. Department of Medical Genetics, Koc University School of Medicine, Istanbul, Turkey
9. Department of Human Genetics, McGill University, Montreal, QC, Canada
10. The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada
11. Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands
12. 3billion Inc, Seoul, South Korea
13. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
14. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
15. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
16. Laboratory of Lipid Biochemistry and Protein Interactions (LIPIT), Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
17. Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands
18. Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran

Source: Human Molecular Genetics Published:2022

Abstract

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. © 2022 The Author(s). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Style	Citing Format
MLA	Paul F, et al.. "Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder." Human Molecular Genetics, vol. 31, no. 21, 2022, pp. 3729-3740.
APA	Paul F, Ng C, Mohamad Sahari UB, Nafissi S, Nilipoor Y, Tavasoli AR, Bonnard C, Wong PM, Nabavizadeh N, Altunoglu U, Estiar MA, Majoie CB, Lee H, Nelson SF, Ganor Z, Rouleau GA, Van Veldhoven PP, Massie R, Hennekam RC, ... Reversade B (2022). Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder. Human Molecular Genetics, 31(21), 3729-3740.
Chicago	Paul F, Ng C, Mohamad Sahari UB, Nafissi S, Nilipoor Y, Tavasoli AR, Bonnard C, et al.. "Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder." Human Molecular Genetics 31, no. 21 (2022): 3729-3740.
Harvard	Paul F et al. (2022) 'Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder', Human Molecular Genetics, 31(21), pp. 3729-3740.
Vancouver	Paul F, Ng C, Mohamad Sahari UB, Nafissi S, Nilipoor Y, Tavasoli AR, et al.. Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder. Human Molecular Genetics. 2022;31(21):3729-3740.
BibTex	@article{ author = {Paul F and Ng C and Mohamad Sahari UB and Nafissi S and Nilipoor Y and Tavasoli AR and Bonnard C and Wong PM and Nabavizadeh N and Altunoglu U and Estiar MA and Majoie CB and Lee H and Nelson SF and Ganor Z and Rouleau GA and Van Veldhoven PP and Massie R and Hennekam RC and Kariminejad A and Reversade B}, title = {Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder}, journal = {Human Molecular Genetics}, volume = {31}, number = {21}, pages = {3729-3740}, year = {2022} }
RIS	TY - JOUR AU - Paul F AU - Ng C AU - Mohamad Sahari UB AU - Nafissi S AU - Nilipoor Y AU - Tavasoli AR AU - Bonnard C AU - Wong PM AU - Nabavizadeh N AU - Altunoglu U AU - Estiar MA AU - Majoie CB AU - Lee H AU - Nelson SF AU - Ganor Z AU - Rouleau GA AU - Van Veldhoven PP AU - Massie R AU - Hennekam RC AU - Kariminejad A AU - Reversade B TI - Rabenosyn Separation-Of-Function Mutations Uncouple Endosomal Recycling From Lysosomal Degradation, Causing a Distinct Mendelian Disorder JO - Human Molecular Genetics VL - 31 IS - 21 SP - 3729 EP - 3740 PY - 2022 ER -

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