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Lookup NU author(s): Andrew Browning
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s)Inherited retinal diseases (IRDs) are a genetically heterogeneous group of Mendelian disorders that often lead to progressive vision loss and involve approximately 300 distinct genes. Although variants in these loci account for the majority of molecular diagnoses, other genes associated with IRD await molecular identification. In this study, we uncover bi-allelic assortments of 23 different (22 loss-of-function) variants in AP5Z1, AP5M1, and AP5B1 as independent causes of recessive IRD in members of 19 families from nine countries. Affected individuals, regardless of their genotypes, exhibit a specific form of macular degeneration, sometimes presenting in association with extraocular features. All three genes encode different subunits of the vesicular fifth adaptor protein (AP-5) complex, a component of the intracellular trafficking system involved in maintaining cellular homeostasis and ensuring the proper functioning of lysosomal pathways. The retinal pigment epithelium (RPE), a cellular monolayer located posteriorly to the neural retina, is characterized by intense lysosomal and phagocytic activity. Immunostaining of RPE cells revealed a punctate pattern of AP5Z1, AP5M1, and AP5B1 staining and co-localization with markers of late endosomes and the Golgi, suggesting a role of AP-5 in the normal physiology of this tissue. Overall, the identification of independently acting variants in three distinct proteins within the same macromolecular complex reveals AP-5 as having an important function in the preservation and maintenance of normal macular functions.
Author(s): Kaminska K, Cancellieri F, Quinodoz M, Moye AR, Bauwens M, Lin S, Janeschitz-Kriegl L, Hayman T, Barberan-Martinez P, Schlaeger R, Van den Broeck F, Avila Fernandez A, Fernandez-Caballero L, Perea-Romero I, Garcia-Garcia G, Salom D, Mazzola P, Zuleger T, Poths K, Haack TB, Jacob J, Vermeer S, Terbeek F, Feltgen N, Moulin AP, Koutroumanou L, Papadakis G, Browning AC, Madhusudhan S, Granse L, Banin E, Sousa AB, Coutinho Santos L, Kuehlewein L, De Angeli P, Leroy BP, Mahroo OA, Sedgwick F, Eden J, Pfau M, Andreasson S, Scholl HPN, Ayuso C, Millan JM, Sharon D, Tsilimbaris MK, Vaclavik V, Tran HV, Ben-Yosef T, De Baere E, Webster AR, Arno G, Sergouniotis PI, Kohl S, Santos C, Rivolta C
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2025
Volume: 112
Issue: 4
Pages: 808-828
Print publication date: 03/04/2025
Online publication date: 12/03/2025
Acceptance date: 13/02/2025
Date deposited: 07/04/2025
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2025.02.015
DOI: 10.1016/j.ajhg.2025.02.015
Data Access Statement: Data and code availability All variants identified in this study have been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/).
PubMed id: 40081374
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