Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent Than Expected in the UK Population
Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent Than Expected in the UK Population
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DOI：
10.1016/j.ajhg.2013.01.011
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发表时间：
2013-03-07
影响因子：
9.8
通讯作者：
Mead, Simon
中科院分区：
文献类型：
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作者：
Beck, Jon;Poulter, Mark;Mead, Simon
C9 orf 72中的六核苷酸重复扩增是额颞叶变性（FTLD）和肌萎缩侧索硬化（ALS）的主要原因。由于难以估计扩增大小，因此阻碍了对疾病机制的理解和临床诊断基因分型的方法。我们发现了96个重复引物PCR扩增：在6个神经退行性疾病队列（FTLD、ALS、阿尔茨海默病、散发性克雅氏病、亨廷顿病样综合征和其他非特异性神经退行性疾病综合征）中有85/2，974，在英国1958年出生队列（58 BC）对照中有11/7，579（0.15%）。使用改良的Southern印迹方法，病例的估计扩展范围（涂片最大值）为800- 4，400。同样，在群体对照中检测到大量扩增。在来自组织和细胞系的DNA样品之间检测到扩增大小和形态的差异。在重复引物PCR检测到扩增的那些人中，68/69通过印迹法确认，印迹法特异于大于275个重复。我们发现，在不同的个体和同一个人的不同脑区之间的扩张涂片的形态变化。扩张的大小与临床发病时的年龄相关，但在诊断组之间没有差异。在控制家庭，以及相邻的SNP和微卫星分析的重复序列大小的不稳定性的证据，支持在同一单倍型背景的多个扩展事件。我们的方法估计大扩张的大小具有潜在的临床实用性。C9 orf 72相关疾病可能类似于几种神经退行性疾病，在英国可能有90，000名携带者，比以前认识到的更常见。
Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.