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Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy

2025-04Artigo científico Acesso aberto
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dc.contributor.authorKaminska, Karolina
dc.contributor.authorCancellieri, Francesca
dc.contributor.authorQuinodoz, Mathieu
dc.contributor.authorMoye, Abigail R.
dc.contributor.authorBauwens, Miriam
dc.contributor.authorLin, Siying
dc.contributor.authorJaneschitz-Kriegl, Lucas
dc.contributor.authorHayman, Tamar
dc.contributor.authorBarberán-Martínez, Pilar
dc.contributor.authorSchlaeger, Regina
dc.contributor.authorVan den Broeck, Filip
dc.contributor.authorÁvila Fernández, Almudena
dc.contributor.authorFernández-Caballero, Lidia
dc.contributor.authorPerea-Romero, Irene
dc.contributor.authorGarcía-García, Gema
dc.contributor.authorSalom, David
dc.contributor.authorMazzola, Pascale
dc.contributor.authorZuleger, Theresia
dc.contributor.authorPoths, Karin
dc.contributor.authorHaack, Tobias B.
dc.contributor.authorJacob, Julie
dc.contributor.authorVermeer, Sascha
dc.contributor.authorTerbeek, Frédérique
dc.contributor.authorFeltgen, Nicolas
dc.contributor.authorMoulin, Alexandre P.
dc.contributor.authorKoutroumanou, Louisa
dc.contributor.authorPapadakis, George
dc.contributor.authorBrowning, Andrew C.
dc.contributor.authorMadhusudhan, Savita
dc.contributor.authorGränse, Lotta
dc.contributor.authorBanin, Eyal
dc.contributor.authorSousa, Ana Berta
dc.contributor.authorCoutinho Santos, Luisa
dc.contributor.authorKuehlewein, Laura
dc.contributor.authorDe Angeli, Pietro
dc.contributor.authorLeroy, Bart P.
dc.contributor.authorMahroo, Omar A.
dc.contributor.authorSedgwick, Fay
dc.contributor.authorEden, James
dc.contributor.authorPfau, Maximilian
dc.contributor.authorAndréasson, Sten
dc.contributor.authorScholl, Hendrik P.N.
dc.contributor.authorAyuso, Carmen
dc.contributor.authorMillán, José M.
dc.contributor.authorSharon, Dror
dc.contributor.authorTsilimbaris, Miltiadis K.
dc.contributor.authorVaclavik, Veronika
dc.contributor.authorTran, Hoai V.
dc.contributor.authorBen-Yosef, Tamar
dc.contributor.authorDe Baere, Elfride
dc.contributor.authorWebster, Andrew R.
dc.contributor.authorArno, Gavin
dc.contributor.authorSergouniotis, Panagiotis I.
dc.contributor.authorKohl, Susanne
dc.contributor.authorSantos, Cristina
dc.contributor.authorRivolta, Carlo
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutioniNOVA4Health - pólo NMS
dc.contributor.pblCell Press
dc.date.accessioned2025-04-10T15:58:53Z
dc.date.available2025-04-10T15:58:53Z
dc.date.issued2025-04
dc.descriptionFunding Information: This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust , Cancer Research UK , and the Medical Research Council have also funded research infrastructure. Publisher Copyright: © 2025 The Author(s)
dc.description.abstractInherited 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent6840193
dc.identifier.doi10.1016/j.ajhg.2025.02.015
dc.identifier.issn0002-9297
dc.identifier.otherPURE: 114067745
dc.identifier.otherPURE UUID: 6315856b-9927-444a-b3d3-c2ee6b6c59f1
dc.identifier.otherScopus: 105000036176
dc.identifier.urihttp://hdl.handle.net/10362/182054
dc.identifier.urlhttps://www.scopus.com/pages/publications/105000036176
dc.language.isoeng
dc.peerreviewedyes
dc.subjectadaptor protein complex 5
dc.subjectAP-5
dc.subjectAP5B1
dc.subjectAP5M1
dc.subjectAP5Z1
dc.subjectinherited retinal diseases
dc.subjectmacular dystrophy
dc.subjectGenetics
dc.subjectGenetics(clinical)
dc.titleBi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophyen
dc.typejournal article
degois.publication.firstPage808
degois.publication.issue4
degois.publication.lastPage828
degois.publication.titleAmerican journal of human genetics
degois.publication.volume112
dspace.entity.typePublication
rcaap.rightsopenAccess

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