Correlating the Expression and Functional Activity ofABCA4 Disease Variants With the Phenotype of PatientsWith Stargardt Disease

Investigative Ophthalmology & Visual Science

article

Robert S. Molday¹  Fabian Garces¹  Kailun Jiang²  Laurie L. Molday¹  Heidi Stöhr³  Bernhard H. Weber³  Christopher J. Lyons²  David Maberley² 

[1] Department of Biochemistry and Molecular Biology, University of British Columbia;Department of Ophthalmology and Visual Sciences, University of British Columbia;Institute of Human Genetics, University of Regensburg

关键词: Stargardt disease;    ABCA4;    protein expression;    phenotype-genotype;    functionalactivity;   

DOI  :  10.1167/iovs.17-23364

学科分类：社会科学、人文和艺术（综合）

来源: Association for Research in Vision and Ophthalmology

【 摘 要 】

PURPOSE. Stargardt disease (STGD1), the most common early-onset recessive maculardegeneration, is caused by mutations in the gene encoding the ATP-binding cassettetransporter ABCA4. Although extensive genetic studies have identified more than 1000mutations that cause STGD1 and related ABCA4-associated diseases, few studies haveinvestigated the extent to which mutations affect the biochemical properties of ABCA4. Thepurpose of this study was to correlate the expression and functional activities of missensemutations in ABCA4 identified in a cohort of Canadian patients with their clinical phenotype.METHODS. Eleven patients from British Columbia were diagnosed with STGD1. The exons andexon-intron boundaries were sequenced to identify potential pathologic mutations in ABCA4.Missense mutations were expressed in HEK293T cells and their level of expression, retinoidsubstrate binding properties, and ATPase activities were measured and correlated with thephenotype of the STGD1 patients.RESULTS. Of the 11 STGD1 patients analyzed, 7 patients had two mutations in ABCA4, 3patients had one detected mutation, and 1 patient had no mutations in the exons and flankingregions. Included in this cohort of patients was a severely affected 11-year-old child who washomozygous for the novel p.Ala1794Pro mutation. Expression and functional analysis of thisvariant and other disease-associated variants compared favorably with the phenotypes of thiscohort of STGD1 patients.CONCLUSIONS. Although many factors contribute to the phenotype of STGD1 patients, theexpression and residual activity of ABCA4 mutants play a major role in determining thedisease severity of STGD1 patients.

【 授权许可】

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