June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Identification and characterization of a novel retina-specific lncRNA upstream ABCA4 with a potential role in ABCA4-associated inherited retinal disease
Author Affiliations & Notes
  • Alfredo Dueñas Rey
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Víctor López-Soriano
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Zelia Corradi
    Radboudumc Department of Human Genetics, Nijmegen, Gelderland, Netherlands
  • Claire-Marie Dhaenens
    Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France
  • Manon Bouckaert
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Jasper Verwilt
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
    OncoRNALab, Cancer Research Institute Ghent, Ghent, Belgium
  • Avril M Watson
    Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • Majlinda Lako
    Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • Eva D’haene
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Karla Alejandra Ruiz Ceja
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Sandro Banfi
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Miriam Bauwens
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Frans P Cremers
    Radboudumc Department of Human Genetics, Nijmegen, Gelderland, Netherlands
  • Steve Lefever
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Elfride De Baere
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Frauke Coppieters
    Universitair Ziekenhuis Gent Centrum Medische Genetica Gent, Gent, Belgium
    Department of Biomolecular Medicine, Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, Belgium
  • Footnotes
    Commercial Relationships   Alfredo Dueñas Rey None; Víctor López-Soriano None; Zelia Corradi None; Claire-Marie Dhaenens None; Manon Bouckaert None; Jasper Verwilt None; Avril Watson None; Majlinda Lako None; Eva D’haene None; Karla Alejandra Ruiz Ceja None; Sandro Banfi None; Miriam Bauwens None; Frans Cremers None; Steve Lefever None; Elfride De Baere None; Frauke Coppieters None
  • Footnotes
    Support  StarT (H2020-MSCA-ITN-2018); Fondation JED; ARVO EyeFind
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2628. doi:
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      Alfredo Dueñas Rey, Víctor López-Soriano, Zelia Corradi, Claire-Marie Dhaenens, Manon Bouckaert, Jasper Verwilt, Avril M Watson, Majlinda Lako, Eva D’haene, Karla Alejandra Ruiz Ceja, Sandro Banfi, Miriam Bauwens, Frans P Cremers, Steve Lefever, Elfride De Baere, Frauke Coppieters; Identification and characterization of a novel retina-specific lncRNA upstream ABCA4 with a potential role in ABCA4-associated inherited retinal disease. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2628.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Inherited retinal diseases (IRDs) are a major cause of early-onset vision loss. While mutations in coding regions explain 60% of IRDs, non-coding variants can be a source of missing heritability. A major knowledge-gap lies in the role of long non-coding RNAs (lncRNAs), highly tissue-specific molecules that regulate gene expression at the right time and place. However, little is known about their function in the retina. Here we identified a novel retina-specific lncRNA located upstream ABCA4, the gene implicated in Stargardt (STGD1) disease.

Methods : Expression specificity was determined by re-analysis of published short-read RNAseq data (GTEx, adult human retina, retinal organoids) as well as single-cell data (adult human retina). Long-read sequencing on adult human retina was performed using nanopore sequencing (PCR-cDNA kit, PromethION, ONT). Single-molecule RNA in situ hybridization (RNAScope/BaseScope) was conducted to elucidate cell-type expression. Chromatin interaction profiles (UMI-4C) were generated to evaluate interaction with the ABCA4 promoter. Genomic variation was evaluated in smMIPS data of the ABCA4 locus in 1,054 STGD1 cases.

Results : Short-read RNAseq analysis of ~7,400 transcriptomes of 54 tissues (GTEx) and 152 transcriptomes of adult human retinas revealed a potential novel lncRNA upstream of ABCA4, with expression restricted to the human retina. Long-read sequencing of donor retina identified at least two novel multi-exonic isoforms, for which expression was demonstrated in the outer nuclear layer of adult human retina. The lncRNA is transcribed from an active retinal enhancer interacting with the ABCA4 promoter, suggesting a cis-acting effect on ABCA4. In smMIPS data from 1,054 STGD1 cases we identified 5 heterozygous novel copy number variants overlapping the lncRNA, representing likely pathogenic or modifying alleles. Perturbation knockdown studies in human retinal explants are ongoing to further elucidate its function.

Conclusions : We identified and characterized a novel retina-specific lncRNA, potentially implicated in ABCA4-associated IRD. This study provides novel insight into the role of this lncRNA - an unexplored class of molecule in the retina field - in gene regulation and IRD pathogenesis, which may ultimately entail therapeutic perspectives.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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