| Autor: |
Cooper-Knock, Johnathan, Zhang, Sai, Kenna, Kevin P., Moll, Tobias, Franklin, John P., Allen, Samantha, Nezhad, Helia Ghahremani, 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, Blair, Ian, Wray, Naomi, Kiernan, Matthew, Neto, Miguel Mitne, Chio, Adriano, Cauchi, Ruben, Robberecht, Wim, van Damme, Philip, Corcia, Phillippe, Couratier, Phillipe, Hardiman, Orla, McLaughlin, Russel, Gotkine, Marc, Drory, Vivan, Ticozzi, Nicola, Silani, Vincenzo, Veldink, Jan, van den Berg, Leonard, de Carvalho, Mamede, Pardina, Jesus Mora, Povedano, Monica, Andersen, Peter, Wber, Markus, Başak, Nazli, Al-Chalabi, Ammar, Shaw, Christopher, Shaw, Pamela, Morrison, Karen, Landers, John, Glass, Jonathan, Veldink, Jan H., Kirby, Janine, Snyder, Michael P., Shaw, Pamela J. |
| Zdroj: |
Cell Reports; December 2020, Vol. 33 Issue: 9 |
| Abstrakt: |
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/CAV2enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2expression in neurons. Additional enrichment of ALS-associated mutations within CAV1exons positions CAV1as an ALS risk gene. We propose CAV1/CAV2overexpression as a personalized medicine target for ALS. |
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