Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia
Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia
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DOI：
10.1093/hmg/ddt460
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发表时间：
2014-02-01
影响因子：
3.5
通讯作者：
Clarimon, Jordi
中科院分区：
文献类型：
--
作者：
Dols-Icardo, Oriol;Garcia-Redondo, Alberto;Clarimon, Jordi
C9orf72基因内的六核苷酸重复序列扩张是肌萎缩侧索硬化症(ALS)和额颞痴呆(FTD)的最重要的遗传原因。开发一种精确的方法来确定扩增大小的困难阻碍了对六核苷酸重复数与临床表型之间可能的相关性的研究。在这里，我们通过一种新的非放射性Southern印迹方法，表征了一系列38个ALS和22个FTD杂合携带者的>；30重复拷贝的扩展大小范围。ALS患者的最大六核苷酸重复数、中位数和模式六核苷酸重复数均高于FTD患者(P<；0.05)。重复数中位数越高，重复数范围越大(Spearman‘s Rho=0.743，P=1.05x10(-11))。在ALS和FTD突变携带者中，我们都没有发现发病年龄或病程与重复大小之间的任何关联。ALS患者的临床表现(球部或脊柱)也与重复长度无关。最后，我们分析了两个受影响和未受影响的重复扩增携带者的家系，比较了两个同卵双胞胎(一个受ALS影响，另一个未受影响)的重复扩增大小，并检测了同一FTD患者的两个不同组织(小脑和外周血)的重复扩增大小。结果表明，C9orf72重复序列的长度在包括MZ双胞胎在内的家庭成员之间以及同一个体的不同组织之间存在差异。
Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P < 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's rho = 0.743, P = 1.05 x 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.