Repeat expansion diseases.
Repeat expansion diseases.
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重复扩张疾病。
DOI：
10.1016/b978-0-444-63233-3.00009-9
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发表时间：
2018
影响因子：
--
通讯作者：
Paulson H
中科院分区：
文献类型：
--
作者：
Paulson H
超过40种疾病，其中大多数主要影响神经系统，是由分散在整个人类基因组中的简单序列重复序列的扩展引起的。扩展三核苷酸重复疾病是最早发现的，并且仍然是最常见的。最近，四，五，六，甚至十二核苷酸重复扩增已被确定为人类疾病的原因，包括神经学家看到的一些最常见的遗传疾病。重复扩增疾病包括强直性肌营养不良（DM 1和DM 2）的两种原因、肌萎缩性侧索硬化/额颞叶痴呆（C9 ORF 72）的最常见遗传原因、亨廷顿病和八种其他多聚谷氨酰胺病症，包括最常见形式的显性遗传性共济失调、最常见的隐性共济失调（弗里德赖希共济失调）和最常见的遗传性精神发育迟滞（脆性X综合征）。在这里，我回顾了这组疾病的独特特征，这些特征源于潜在突变的不寻常的动态性质。这些特征包括显著的临床异质性和临床预期现象。然后，我讨论了不同的分子机制驱动疾病的发病机制，这取决于重复序列，大小和疾病基因内的位置，以及是否重复翻译成蛋白质。最后，我简要介绍了与神经科医生最相关的个体重复扩增疾病的临床和遗传学描述。
More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa- and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease and eight other polyglutamine disorders including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (Fragile X Syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.