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https://www.um.edu.mt/library/oar/handle/123456789/103518
Title: | Rare variant burden analysis within enhancers identifies CAV1 as an ALS risk gene |
Authors: | Cooper-Knock, Johnathan Zhang, Sai Kenna, Kevin P. Moll, Tobias Franklin, John P. Allen, Samantha Ghahremani Nezhad, Helia Iacoangeli, Alfredo Yacovzada, Nancy Y. Eitan, Chen Hornstein, Eran Elhaik, Eran Celadova, Petra Bose, Daniel Farhan, Sali Fishilevich, Simon Lancet, Doron Morrison, Karen E. Shaw, Christopher E. Al-Chalabi, Ammar Veldink, Jan H. Kirby, Janine Snyder, Michael P. Shaw, Pamela J. Cauchi, Ruben J. |
Authors: | Project MinE ALS Sequencing Consortium |
Keywords: | Amyotrophic lateral sclerosis -- Diagnosis Genes Non-coding RNA Gene expression Membrane lipids -- Research |
Issue Date: | 2020 |
Publisher: | Cell Press |
Citation: | Cooper-Knock, J., Zhang, S., Kenna, K. P., Moll, T., Franklin, J. P., Allen, S.,...Shaw, P. J. (2020). Rare variant burden analysis within enhancers identifies CAV1 as an ALS risk gene. Cell reports, 33(9), 108456. |
Abstract: | Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS. |
URI: | https://www.um.edu.mt/library/oar/handle/123456789/103518 |
Appears in Collections: | Scholarly Works - FacM&SPB |
Files in This Item:
File | Description | Size | Format | |
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Rare_variant_burden_analysis_within_enhancers_identifies_CAV1_as_an_ALS_risk_gene.pdf | 1.72 MB | Adobe PDF | View/Open |
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