基因扩展
The Genetics of Expansions.
机构信息
Department of Molecular Genetics, VIB, University of Antwerp, 2610 Antwerp, Belgium.
Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
出版信息
Cold Spring Harb Perspect Med. 2018 Apr 2;8(4):a026757. doi: 10.1101/cshperspect.a026757.
Abstract
Repeat expansions in the promoter region of are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and related disorders of the ALS/frontotemporal lobar degeneration (FTLD) spectrum. Remarkable clinical heterogeneity among patients with a repeat expansion has been observed, and genetic anticipation over different generations has been suggested. Genetic factors modifying the clinical phenotype have been proposed, including genetic variation in other known disease genes, the genomic context of the repeat, and expanded repeat size, which has been estimated between 45 and several thousand units. The role of variability in normal and expanded repeat sizes for disease risk and clinical phenotype is under debate. Different pathogenic mechanisms have been proposed, including loss of function, RNA toxicity, and dipeptide repeat (DPR) protein toxicity resulting from abnormal translation of the expanded repeat, but the major mechanism is yet unclear.
摘要
重复扩展是肌萎缩侧索硬化症（ALS）和相关 ALS/额颞叶变性（FTLD）谱疾病的最常见遗传原因。已经观察到具有重复扩展的患者之间存在显著的临床异质性，并且已经提出了不同代之间的遗传预期。已经提出了修饰临床表型的遗传因素，包括其他已知疾病基因中的遗传变异、重复扩展的基因组背景和扩展的重复大小，其估计在 45 到几千个单位之间。正常和扩展的重复大小的变异性对疾病风险和临床表型的作用仍存在争议。已经提出了不同的发病机制，包括功能丧失、RNA 毒性和由扩展重复的异常翻译引起的二肽重复（DPR）蛋白毒性，但主要机制尚不清楚。
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本文引用的文献
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Disease Mechanisms of Repeat Expansions.重复扩展的疾病机制。
Cold Spring Harb Perspect Med. 2018 Apr 2;8(4):a024224. doi: 10.1101/cshperspect.a024224.
2
Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD.果蝇筛选将核转运基因与c9ALS/FTD中的DPR病理学联系起来。
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Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide (G₄C₂) repeat expansion in C9orf72 gene.一个同时存在SQSTM1突变和C9orf72基因六核苷酸（G₄C₂）重复扩增的额颞叶痴呆-进行性核上性麻痹家族的特征分析
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Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort.在比利时队列中，与C9orf72、GRN突变携带者及非突变携带者相比，TBK1突变携带者的临床特征。
Brain. 2016 Feb;139(Pt 2):452-67. doi: 10.1093/brain/awv358. Epub 2015 Dec 15.
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The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter.C9orf72重复序列大小与疾病发病年龄、启动子的DNA甲基化及转录下调相关。
Mol Psychiatry. 2016 Aug;21(8):1112-24. doi: 10.1038/mp.2015.159. Epub 2015 Oct 20.
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Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS.C9orf72二肽重复毒性的调节剂将核质运输缺陷与额颞叶痴呆/肌萎缩侧索硬化症联系起来。
Nat Neurosci. 2015 Sep;18(9):1226-9. doi: 10.1038/nn.4085.
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Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease.全基因组测序揭示TBK1和OPTN突变在无运动神经元病的额颞叶痴呆中的重要作用。
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Nat Neurosci. 2015 May;18(5):631-6. doi: 10.1038/nn.4000. Epub 2015 Mar 24.
9
C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence.C9orf72启动子高甲基化具有神经保护作用：神经影像学和神经病理学证据。
Neurology. 2015 Apr 21;84(16):1622-30. doi: 10.1212/WNL.0000000000001495. Epub 2015 Mar 20.
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The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients.C9orf72 重复扩展本身在 ALS 和额颞叶痴呆患者中被甲基化。
Acta Neuropathol. 2015 May;129(5):715-27. doi: 10.1007/s00401-015-1401-8. Epub 2015 Feb 26.
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