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Clark, Michael B., Wrzesinski, Tomasz, Garcia, Aintzane B., Hall, Nicola A. L., Kleinman, Joel E., Hyde, Thomas, Weinberger, Daniel R., Harrison, Paul J., Haerty, Wilfried 
ORCID: https://orcid.org/0000-0003-0111-191X and Tunbridge, Elizabeth M.
(2020)
Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain.
Molecular Psychiatry, 25 (1).
pp. 37-47.
ISSN 1359-4184
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Abstract
RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show that CACNA1C’s transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.
| Item Type: | Article |
|---|---|
| Faculty \ School: | Faculty of Science > School of Biological Sciences |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 30 Jan 2021 01:11 |
| Last Modified: | 21 Apr 2023 00:54 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/78331 |
| DOI: | 10.1038/s41380-019-0583-1 |
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