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Lookup NU author(s): Miguel Barroso Gil, Dr Eric OlingerORCiD, Dr Simon RamsbottomORCiD, Dr Elisa MolinariORCiD, Dr Colin Miles, Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. Background: Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via tissue-specific preservation of the amount of expressed functional protein. Methods: We systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120- and CC2D2A-associated disease and we combined in silico and ex vivo approaches to study tissue-specific transcripts and identify molecular targets for exon skipping. Results: We confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ-specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. Conclusion: Genotype-phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.
Author(s): Barroso-Gil M, Olinger E, Ramsbottom SA, Molinari E, Miles CG, Sayer JA
Publication type: Article
Publication status: Published
Journal: Molecular Genetics and Genomic Medicine
Year: 2021
Volume: 9
Issue: 12
Print publication date: 01/12/2021
Online publication date: 24/01/2021
Acceptance date: 04/01/2021
Date deposited: 04/11/2021
ISSN (electronic): 2324-9269
Publisher: Wiley-Blackwell
URL: https://doi.org/10.1002/mgg3.1603
DOI: 10.1002/mgg3.1603
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