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Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration

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...

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Autores principales: Garces, Fabian A., Scortecci, Jessica F., Molday, Robert S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796138/
https://www.ncbi.nlm.nih.gov/pubmed/33375396
http://dx.doi.org/10.3390/ijms22010185
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author Garces, Fabian A.
Scortecci, Jessica F.
Molday, Robert S.
author_facet Garces, Fabian A.
Scortecci, Jessica F.
Molday, Robert S.
author_sort Garces, Fabian A.
collection PubMed
description 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.
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spelling pubmed-77961382021-01-10 Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration Garces, Fabian A. Scortecci, Jessica F. Molday, Robert S. Int J Mol Sci Article 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. MDPI 2020-12-27 /pmc/articles/PMC7796138/ /pubmed/33375396 http://dx.doi.org/10.3390/ijms22010185 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Garces, Fabian A.
Scortecci, Jessica F.
Molday, Robert S.
Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
title Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
title_full Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
title_fullStr Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
title_full_unstemmed Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
title_short Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
title_sort functional characterization of abca4 missense variants linked to stargardt macular degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796138/
https://www.ncbi.nlm.nih.gov/pubmed/33375396
http://dx.doi.org/10.3390/ijms22010185
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