Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations

Zhang, Ning, Tsybovsky, Yaroslav, Kolesnikov, Alexander V., Rozanowska, Malgorzata, Swider, Malgorzata, Schwartz, Sharon B., Stone, Edwin M., Palczewska, Grazyna, Maeda, Akiko, Kefalov, Vladimar J., Jacobson, Samuel G., Cideciyan, Artur V. and Palczewski, Krzysztof 2015. Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. Human Molecular Genetics 24 (11) , pp. 3220-3237. 10.1093/hmg/ddv073

Full text not available from this repository.


Mutations in the ABCA4 gene are a common cause of autosomal recessive retinal degeneration. All mouse models to date are based on knockouts of Abca4, even though the disease is often caused by missense mutations such as the complex allele L541P;A1038V (PV). We now show that the PV mutation causes severe human disease whereas the V mutation alone causes mild disease. Mutant ABCA4 proteins expressed heterologously in mammalian cells retained normal cellular localization. However, basal and all-trans-retinal-stimulated ATPase activities were reduced substantially for P and PV but only mildly for V. Electron microscopy revealed marked structural changes and misfolding for the P and PV mutants but few changes for the V mutant, consistent with the disease severity difference in patients. We generated Abca4PV/PV knock-in mice homozygous for the complex PV allele to investigate the effects of this misfolding mutation in vivo. Mutant ABCA4 RNA levels approximated WT ABCA4 RNA levels but, surprisingly, only trace amounts of mutant ABCA4 protein were noted in the retina. RNA sequencing of WT, Abca4−/− and Abca4PV/PV mice revealed mild gene expression alterations in the retina and RPE. Similar to Abca4−/− mice, Abca4PV/PV mice showed substantial A2E and lipofuscin accumulation in their RPE cells but no retinal degeneration up to 12 months of age. Thus, rapid degradation of this large misfolded mutant protein in mouse retina caused little detectable photoreceptor degeneration. These findings suggest likely differences in the unfolded protein response between murine and human photoreceptors and support development of therapies directed at increasing this capability in patients.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Optometry and Vision Sciences
Publisher: Oxford University Press
ISSN: 0964-6906
Funders: National Institutes of Health, the Research to Prevent Blindness Foundation, Foundation Fighting Blindness, and Fight for Sight, the Ohio Lions Eye Research Foundation, the Knights Templar Eye Foundation
Date of Acceptance: 22 February 2015
Last Modified: 05 Nov 2020 17:45

Citation Data

Cited 51 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item