Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy
Kaminska, K. ; Gränse, L. LU
; Andréasson, S.
LU
and Rivolta, C.
(2025)
In American Journal of Human Genetics
112(4).
p.808-828
- Abstract
- 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... (More)
- 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. © 2025 The Author(s) (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/48291881-131e-4852-ab12-d9cfc4123b1b
- author
- Kaminska, K.
; Gränse, L.
LU
; Andréasson, S.
LU
and Rivolta, C.
- author collaboration
- organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- adaptor protein complex 5, AP-5, AP5B1, AP5M1, AP5Z1, inherited retinal diseases, macular dystrophy
- in
- American Journal of Human Genetics
- volume
- 112
- issue
- 4
- pages
- 21 pages
- publisher
- Cell Press
- external identifiers
-
- scopus:105000036176
- pmid:40081374
- ISSN
- 0002-9297
- DOI
- 10.1016/j.ajhg.2025.02.015
- language
- English
- LU publication?
- yes
- id
- 48291881-131e-4852-ab12-d9cfc4123b1b
- date added to LUP
- 2025-12-17 16:49:07
- date last changed
- 2025-12-18 03:00:04
@article{48291881-131e-4852-ab12-d9cfc4123b1b,
abstract = {{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. © 2025 The Author(s)}},
author = {{Kaminska, K. and Gränse, L. and Andréasson, S. and Rivolta, C.}},
issn = {{0002-9297}},
keywords = {{adaptor protein complex 5; AP-5; AP5B1; AP5M1; AP5Z1; inherited retinal diseases; macular dystrophy}},
language = {{eng}},
number = {{4}},
pages = {{808--828}},
publisher = {{Cell Press}},
series = {{American Journal of Human Genetics}},
title = {{Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy}},
url = {{http://dx.doi.org/10.1016/j.ajhg.2025.02.015}},
doi = {{10.1016/j.ajhg.2025.02.015}},
volume = {{112}},
year = {{2025}},
}