Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 21, Issue -, Pages 412-427Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2020.06.007
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Funding
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid
- Stichting Blinden-Penning
- Landelijke Stichting voor Blinden en Slechtzienden
- Stichting Oogfonds Nederland
- Stichting Macula Degeneratie Fonds
- Stichting Retina Nederland Fonds [UitZicht 2015-31, 2018-21]
- Rotterdamse Stichting Blindenbelangen
- Stichting Blindenhulp
- Stichting tot Verbetering van het Lot der Blinden
- Stichting voor Ooglijders
- Stichting Dowilvo
- Foundation Fighting Blindness USA [PPA-0517-0717-RAD]
- Retina UK [GR596]
- European Union, Marie Curie Sklodowska Action Initial Training Network StarT [813490]
- National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital
- UCL Institute of Ophthalmology
- NIHR BioResource - Rare Diseases
- Fight For Sight UK Early Career Investigator Award
- NIHR Great Ormond Street Hospital Biomedical Research Centre at Great Ormond Street Institute of Child Health
- Fight for Sight UK
- Wellcome Trust
- Moorfields Eye Charity
- NIHR Bioresource Translational Research Consortium for Rare Disease
- National Institute for Health Research
- NHS England
- Cancer Research UK
- Medical Research Council
- Marie Curie Actions (MSCA) [813490] Funding Source: Marie Curie Actions (MSCA)
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Stargardt disease is a progressive retinal disorder caused by biallelic mutations in the ABCA4 gene that encodes the ATPbinding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.
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