FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat.
FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat.
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DOI：
10.1093/hmg/ddy375
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发表时间：
2019-02-15
影响因子：
3.5
通讯作者：
Tabrizi SJ
中科院分区：
文献类型：
--
作者：
Goold R;Flower M;Moss DH;Medway C;Wood-Kaczmar A;Andre R;Farshim P;Bates GP;Holmans P;Jones L;Tabrizi SJ
亨廷顿病（HD）是由亨廷顿蛋白（HTT）基因中CAG重复序列扩增引起的遗传性神经退行性疾病。CAG重复序列长度解释了发病年龄（AAO）变异的一半左右，但基因组中其他地方的遗传变异占其余变异的很大比例。全基因组关联研究已经确定了15号染色体上的双向信号，可能是由FANCD 2和FANCI相关核酸酶1（FAN1），一种参与DNA链间交联修复的核酸酶。在这里，我们发现FAN1表达增加与AAO延迟和HD进展缓慢显著相关，表明FAN1在HTT CAG重复扩增的背景下具有保护作用。人细胞中FAN1过表达减少了外源表达的突变HTT外显子1中CAG重复扩增，而在患者源性干细胞和分化的中等多刺神经元中，FAN1敲低增加了CAG重复扩增。稳定效应是FAN 1浓度和CAG重复长度依赖性的。我们表明，FAN1结合到扩展的HTT CAG重复DNA和它的核酸酶活性是不需要的保护对CAG重复扩增。这些数据为HD的遗传修饰剂如何改变疾病进展提供了新的机制见解，并表明FAN1通过核酸酶非依赖性机制影响CAG重复序列的体细胞扩增。这为HD和潜在的其他三联体重复疾病的治疗干预提供了新的途径。
Huntington’s disease (HD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the huntingtin (HTT) gene. CAG repeat length explains around half of the variation in age at onset (AAO) but genetic variation elsewhere in the genome accounts for a significant proportion of the remainder. Genome-wide association studies have identified a bidirectional signal on chromosome 15, likely underlain by FANCD2- and FANCI-associated nuclease 1 (FAN1), a nuclease involved in DNA interstrand cross link repair. Here we show that increased FAN1 expression is significantly associated with delayed AAO and slower progression of HD, suggesting FAN1 is protective in the context of an expanded HTT CAG repeat. FAN1 overexpression in human cells reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1, and in patient-derived stem cells and differentiated medium spiny neurons, FAN1 knockdown increases CAG repeat expansion. The stabilizing effects are FAN1 concentration and CAG repeat length-dependent. We show that FAN1 binds to the expanded HTT CAG repeat DNA and its nuclease activity is not required for protection against CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of HD act to alter disease progression and show that FAN1 affects somatic expansion of the CAG repeat through a nuclease-independent mechanism. This provides new avenues for therapeutic interventions in HD and potentially other triplet repeat disorders.
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影响因子：
4.3
作者：
Kaplan S;Itzkovitz S;Shapiro E
通讯作者：
Shapiro E
影响因子：
16.6
作者：
Goold, R.;Rabbanian, S.;Sutton, L.;Andre, R.;Arora, P.;Moonga, J.;Clarke, A. R.;Schiavo, G.;Jat, P.;Collinge, J.;Tabrizi, S. J.
通讯作者：
Tabrizi, S. J.
影响因子：
11.2
作者：
Bettencourt C;Hensman-Moss D;Flower M;Wiethoff S;Brice A;Goizet C;Stevanin G;Koutsis G;Karadima G;Panas M;Yescas-Gómez P;García-Velázquez LE;Alonso-Vilatela ME;Lima M;Raposo M;Traynor B;Sweeney M;Wood N;Giunti P;SPATAX Network;Durr A;Holmans P;Houlden H;Tabrizi SJ;Jones L
通讯作者：
Jones L
影响因子：
64.5
作者：
Kratz, Katja;Schoepf, Barbara;Jiricny, Josef
通讯作者：
Jiricny, Josef
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium