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Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations

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Cremers, Frans P.M., Lee, Winston, Collin, Rob W.J., Allikmets, Rando·2020·Progress in Retinal and Eye Research
DOI 10.1016/j.preteyeres.2020.100861PMC PMC7544654
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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.

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  • Stargardt disease (STGD1), also known as fundus flavimaculatus or ABCA4-retinopathy, is a progressive disorder of the retina caused by bi-allelic variants in the gene encoding ABCA4, localized on chromosome 1p22.1.

    “Stargardt disease (STGD1), also known as fundus flavimaculatus or ABCA4-retinopathy, is a progressive disorder of the retina caused by bi-allelic variants in the gene that encodes ATP-binding cassette subfamily A member 4 (ABCA4), localized on chromosome 1p22.1.”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [91]

    The Phenocopies section describes STGD1 as an autosomal recessive disease caused by ABCA4 mutations, and Historical perspective connects Stargardt disease with fundus flavimaculatus. However, Historical perspective says the genetic locus was mapped to 1p13; it does not support the claimed location of 1p22.1. No page numbers are available in our copy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • STGD1 is the most frequent retinal dystrophy caused by a single gene and is believed to affect approximately 1 in 8000-10,000 individuals worldwide.

    “It is the most frequent retinal dystrophy caused by a single gene and is believed to affect approximately 1 in 8000–10,000 individuals worldwide [91].”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [91]

    The Historical perspective describes STGD1 as the most common inherited Mendelian eye disorder, and the Family history and inheritance patterns section identifies it as caused by variants in ABCA4. The Future research section reports the often-cited 1-in-8,000–10,000 estimate but says worldwide prevalence is unknown and the estimate was not scientifically determined. The claim omits that important qualification. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Cremers, F. P. M., Lee, W., Collin, R. W. J., & Allikmets, R.
Affiliations
  • Radboud University Nijmegen (NL)
  • Columbia University Irving Medical Center (US)
Corresponding author
  • Cremers, Frans P.M.
  • Allikmets, Rando
ORCID
Venue
Progress in Retinal and Eye Research
Publisher
Elsevier BV
Published
2020-11
Volume
79
Pages
100861
ISSN
1350-9462 (ISSN-L)
DOI
10.1016/j.preteyeres.2020.100861
PMC
PMC7544654
OpenAlex
W3016046095
Cited by
315
References
23
Citations by year
2026: 32 · 2025: 54 · 2024: 58 · 2023: 59 · 2022: 47 · 2021: 50 · 2020: 15
FWCI
4.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Progress in Retinal and Eye Research (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Foundation Fighting Blindness
  • European Commission
  • Retina UK
  • National Eye Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
ABCA4, Stargardt disease, fundus flavimaculatus, cone-rod dystrophy, retinitis pigmentosa, age-related macular degeneration, ABCA4 mutations, deep intronic variants, splice variants, rod photoreceptors, retinal disease, gene therapy, treatment options
MeSH terms
DNA, Humans, Mutation, Phenotype, Retinal Diseases, Genetic Therapy, ATP-Binding Cassette Transporters

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