动态突变与人类疾病：脊髓小脑共济失调（综述）

摘要(中文译文)

过去十年中发现了一种与人类疾病相关的全新突变事件——动态突变。动态突变的分子机制涉及串联排列的核苷酸序列的扩增及代际不稳定性，使其达到病理性的长度，尽管该序列在正常个体中也存在多态性。迄今为止，至少有十四种神经系统疾病与这一现象相关，包括亨廷顿病、齿状核红核苍白球路易体萎缩、脊髓延髓肌萎缩、强直性肌营养不良、脆性X综合征、FRAXE智力障碍以及脊髓小脑共济失调1至3型、6至8型、12型和17型。脊髓小脑共济失调是一组异质性的严重神经退行性迟发性疾病，以平衡和协调能力丧失为特征。大多数脊髓小脑共济失调呈常染色体显性遗传模式，由相应基因编码区内三核苷酸重复序列的代际扩增所驱动。扩增片段被翻译为蛋白质中异常的聚谷氨酰胺 tract，导致核内聚集体的形成，这已被认为是大多数脊髓小脑共济失调型别发病机制的基础。这些疾病的一个显著特征是，该基因在整个大脑以及其他组织中均有表达，但尽管存在特定的细胞变性，却未观察到病理学后果。对该突变事件特征的阐明促进了特异且灵敏的分子检测方法的发展，可直接进行DNA分析，从而有助于确认临床诊断、制定适当的治疗指征以及提供遗传咨询。

Abstract

A completely new mutational event associated with human diseases - the dynamic mutation - was discovered in the last decade. The molecular mechanism underlying dynamic mutation involves the expansion and intergenerational instability of a tandem-arrayed nucleotide sequence that acquire a pathological size, despite its polymorphic occurrence in normal individuals. To date, at least fourteen neurological disorders are associated with this phenomenon, including Huntington's disease (HD), dentatorubral and palidoluysian atrophy (DRPLA), spinobulbar and muscular atrophy (SBMA), myotonic dystrophy (DM), fragile X syndrome, FRAXE mental retardation and spinocerebellar ataxias (SCA) types 1-3, 6-8, 12 and 17. The spinocerebellar ataxias comprise a heterogeneous group of severe neurodegenerative-late onset disorders characterized by loss of balance and coordination. Most of the spinocerebellar ataxias exhibit an autosomal dominant pattern of inheritance and are promoted by the intergenerational expansion of a trinucleotide repeat (CAG)n inside the coding region of the respective gene. The expanded segment is translated into an abnormal polyglutamine tract in the protein, leading to the formation of nuclear aggregates that have been considered the basis of the pathogenesis in most of SCA types. One striking characteristic of these diseases is that the gene is expressed throughout the brain and also in other tissues but no pathological consequences are observed, despite the specific cellular degeneration. The characterization of the mutational event has led to the development of specific and sensitive molecular tests for direct DNA analysis, which allow confirmation of clinical diagnostic and an adequate therapeutic indication as well as genetic counseling.

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