4.5 Review

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

Journal

PROGRESS IN RETINAL AND EYE RESEARCH
Volume 79, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.preteyeres.2020.100861

Keywords

Stargardt disease; ABCA4-associated retinopathy; Allelic heterogeneity; Autofluorescence; Phenocopies; Hypomorphic variant; Penetrance; Splice defects; Pseudoexon; Structural variant; Therapy

Categories

Funding

  1. Retina UK [GR591, GR596]
  2. Fighting Blindness Ireland [FB18CRE]
  3. Horizon 2020, Marie Sklodowska-Curie Innovative Training Network entitled European Training Network to Diagnose, Understand and Treat Stargardt Disease, a Frequent Inherited Blinding Disorder-StarT [813490]
  4. Foundation Fighting Blindness USA [PPA-1218-0751-COLU, PPA-0517-0717-RAD, BR-GE-1018-0738-RAD]
  5. Rotterdamse Stichting Blindenbelangen
  6. Stichting Blindenhulp
  7. Stichting tot Verbetering van het Lot der Blinden
  8. Landelijke Stichting voor Blinden en Slechtzienden
  9. Macula Degeneratie fonds
  10. Stichting Blinden-Penning [2016-12]
  11. National Eye Institute, NIH [R01 EY028203, R01 EY028954, R01 EY029315, R01 EY024091, P30 19007]
  12. Research to Prevent Blindness

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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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