Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene.
Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene.
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增强剂中的罕见变体负担分析将CAV1识别为ALS风险基因。
DOI：
10.1016/j.celrep.2020.108456
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发表时间：
2020-12-01
期刊：
影响因子：
8.8
通讯作者：
Shaw PJ
中科院分区：
文献类型：
--
作者：
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;Project MinE ALS Sequencing Consortium;Veldink JH;Kirby J;Snyder MP;Shaw PJ
肌萎缩侧索硬化症（ALS）是一种无法治愈的神经退行性疾病。CAV 1和CAV 2组织膜脂筏（MLR）对细胞信号传导和神经元存活很重要，CAV 1的过表达改善了体内ALS表型。全基因组关联研究将大部分ALS风险变体定位在非编码基因组内，但由于缺乏适当的工具，进一步表征受到限制。通过设计和应用一个管道来识别负责调节基因表达的增强子元件内的致病性遗传变异，我们识别了CAV 1/CAV 2增强子内的疾病相关变异，这些增强子在一个独立的队列中复制。发现的增强子突变减少了患者来源的细胞中的CAV 1/CAV 2表达并破坏了MLR，并且接近患者突变的CRISPR-Cas9扰动足以减少神经元中的CAV 1/CAV 2表达。在CAV 1外显子内ALS相关突变的额外富集将CAV 1定位为ALS风险基因。我们建议CAV 1/CAV 2过表达作为ALS的个性化药物靶点。在与CAV 1/CAV 2增强子突变相关的增强子和外显子内鉴定的ALS相关风险变体降低基因表达并破坏膜脂筏CRISPR-Cas9增强子的扰动降低神经元中的CAV 1/CAV 2表达Cooper-Knock et al.在与已知ALS基因TBK 1以及CAV 1和CAV 2相连的非编码调控DNA内鉴定肌萎缩性侧索硬化症（ALS）风险变体。疾病相关变异减少了CAV 1/CAV 2的表达并破坏了膜脂筏，从而导致神经营养信号传导。CAV 1编码序列也含有ALS相关突变。
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. Identification of ALS-associated genetic variation within gene enhancers ALS-associated risk variants identified within enhancers and exons linked to CAV1 CAV1/CAV2 enhancer mutations reduce gene expression and disrupt membrane lipid rafts CRISPR-Cas9 perturbation of enhancer reduces CAV1/CAV2 expression in neurons Cooper-Knock et al. identify amyotrophic lateral sclerosis (ALS) risk variants within non-coding regulatory DNA linked to a known ALS gene, TBK1, but also CAV1 and CAV2. Disease-associated variants reduce CAV1/CAV2 expression and disrupt membrane lipid rafts with consequences for neurotrophic signaling. CAV1 coding sequence also contains ALS-associated mutations.
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DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
13.6
作者：
Gaj T;Ojala DS;Ekman FK;Byrne LC;Limsirichai P;Schaffer DV
通讯作者：
Schaffer DV
影响因子：
6.4
作者：
Day CA;Kenworthy AK
通讯作者：
Kenworthy AK
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.