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Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations.
Prog Retin Eye Res. 2020 Apr 09 [Online ahead of print]PR

Abstract

The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types - missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy - clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.

Authors+Show Affiliations

Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9104, 6500 HE, Nijmegen, the Netherlands. Electronic address: frans.cremers@radboudumc.nl.Department of Ophthalmology, Columbia University, New York, NY, 10032, USA; Department of Genetics & Development, Columbia University, New York, NY, 10032, USA.Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9104, 6500 HE, Nijmegen, the Netherlands.Department of Ophthalmology, Columbia University, New York, NY, 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY, 10032, USA. Electronic address: rla22@cumc.columbia.edu.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32278709

Citation

Cremers, Frans P M., et al. "Clinical Spectrum, Genetic Complexity and Therapeutic Approaches for Retinal Disease Caused By ABCA4 Mutations." Progress in Retinal and Eye Research, 2020, p. 100861.
Cremers FPM, Lee W, Collin RWJ, et al. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. 2020.
Cremers, F. P. M., Lee, W., Collin, R. W. J., & Allikmets, R. (2020). Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Progress in Retinal and Eye Research, 100861. https://doi.org/10.1016/j.preteyeres.2020.100861
Cremers FPM, et al. Clinical Spectrum, Genetic Complexity and Therapeutic Approaches for Retinal Disease Caused By ABCA4 Mutations. Prog Retin Eye Res. 2020 Apr 9;100861. PubMed PMID: 32278709.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. AU - Cremers,Frans P M, AU - Lee,Winston, AU - Collin,Rob W J, AU - Allikmets,Rando, Y1 - 2020/04/09/ PY - 2019/12/06/received PY - 2020/03/13/revised PY - 2020/03/18/accepted PY - 2020/4/13/pubmed PY - 2020/4/13/medline PY - 2020/4/13/entrez KW - ABCA4-associated retinopathy KW - Allelic heterogeneity KW - Autofluorescence KW - Hypomorphic variant KW - Penetrance KW - Phenocopies KW - Pseudoexon KW - Splice defects KW - Stargardt disease KW - Structural variant KW - Therapy SP - 100861 EP - 100861 JF - Progress in retinal and eye research JO - Prog Retin Eye Res N2 - The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types - missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy - clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches. SN - 1873-1635 UR - https://www.unboundmedicine.com/medline/citation/32278709/Clinical_spectrum,_genetic_complexity_and_therapeutic_approaches_for_retinal_disease_caused_by_ABCA4_mutations L2 - https://linkinghub.elsevier.com/retrieve/pii/S1350-9462(20)30033-1 DB - PRIME DP - Unbound Medicine ER -
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