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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Cooper-Knock J,Zhang S,Kenna KP,Moll T,Franklin JP,Allen S,Nezhad HG,Iacoangeli A,Yacovzada NY,Eitan C,Hornstein E,Elhaik E,Celadova P,Bose D,Farhan S,Fishilevich S,Lancet D,Morrison KE,Shaw CE,Al-Chalabi A,Projecdoi
10.1016/j.celrep.2020.108456subject
Has Abstractpub_date
2020-12-01 00:00:00pages
108456issue
9issn
2211-1247pii
S2211-1247(20)31445-5journal_volume
33pub_type
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