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Article

Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration

1
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
2
Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC V5Z 3N9, Canada
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(1), 185; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010185
Received: 27 November 2020 / Revised: 23 December 2020 / Accepted: 23 December 2020 / Published: 27 December 2020
ABCA4 is an ATP-binding cassette (ABC) transporter expressed in photoreceptors, where it transports its substrate, N-retinylidene-phosphatidylethanolamine (N-Ret-PE), across outer segment membranes to facilitate the clearance of retinal from photoreceptors. Mutations in ABCA4 cause Stargardt macular degeneration (STGD1), an autosomal recessive disorder characterized by a loss of central vision and the accumulation of bisretinoid compounds. The purpose of this study was to determine the molecular properties of ABCA4 variants harboring disease-causing missense mutations in the transmembrane domains. Thirty-eight variants expressed in culture cells were analyzed for expression, ATPase activities, and substrate binding. On the basis of these properties, the variants were divided into three classes: Class 1 (severe variants) exhibited significantly reduced ABCA4 expression and basal ATPase activity that was not stimulated by its substrate N-Ret-PE; Class 2 (moderate variants) showed a partial reduction in expression and basal ATPase activity that was modestly stimulated by N-Ret-PE; and Class 3 (mild variants) displayed expression and functional properties comparable to normal ABCA4. The p.R653C variant displayed normal expression and basal ATPase activity, but lacked substrate binding and ATPase activation, suggesting that arginine 653 contributes to N-Ret-PE binding. Our classification provides a basis for better understanding genotype–phenotype correlations and evaluating therapeutic treatments for STGD1. View Full-Text
Keywords: ABC transporter; ABCA4; Stargardt macular degeneration; ATPase activity; photoreceptors; inherited retinal diseases; cell expression; molecular modeling ABC transporter; ABCA4; Stargardt macular degeneration; ATPase activity; photoreceptors; inherited retinal diseases; cell expression; molecular modeling
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MDPI and ACS Style

Garces, F.A.; Scortecci, J.F.; Molday, R.S. Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration. Int. J. Mol. Sci. 2021, 22, 185. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010185

AMA Style

Garces FA, Scortecci JF, Molday RS. Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration. International Journal of Molecular Sciences. 2021; 22(1):185. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010185

Chicago/Turabian Style

Garces, Fabian A., Jessica F. Scortecci, and Robert S. Molday 2021. "Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration" International Journal of Molecular Sciences 22, no. 1: 185. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010185

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