He Ji, Tang Lu, Benyamin Beben, Shah Sonia, Hemani Gib, Liu Rong, Ye Shan, Liu Xiaolu, Ma Yan, Zhang Huagang, Cremin Katie, Leo Paul, Wray Naomi R, Visscher Peter M, Xu Huji, Brown Matthew A, Bartlett Perry F, Mangelsdorf Marie, Fan Dongsheng
Department of Neurology, Peking University Third Hospital, Beijing, China; Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia; Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
Department of Neurology, Peking University Third Hospital, Beijing, China.
Neurobiol Aging. 2015 Sep;36(9):2660.e1-8. doi: 10.1016/j.neurobiolaging.2015.06.002. Epub 2015 Jun 9.
A hexanucleotide repeat expansion (HRE) in the C9orf72 gene has been identified as the most common mutation in amyotrophic lateral sclerosis (ALS) among Caucasian populations. We sought to comprehensively evaluate genetic and epigenetic variants of C9orf72 and the contribution of the HRE in Chinese ALS cases. We performed fragment-length and repeat-primed polymerase chain reaction to determine GGGGCC copy number and expansion within the C9orf72 gene in 1092 sporadic ALS (sALS) and 1062 controls from China. We performed haplotype analysis of 23 single-nucleotide polymorphisms within and surrounding C9orf72. The C9orf72 HRE was found in 3 sALS patients (0.3%) but not in control subjects (p = 0.25). For 2 of the cases with the HRE, genotypes of 8 single-nucleotide polymorphisms flanking the HRE were inconsistent with the haplotype reported to be strongly associated with ALS in Caucasian populations. For these 2 individuals, we found hypermethylation of the CpG island upstream of the repeat, an observation not detected in other sALS patients (p < 10(-8)) or controls. The detailed analysis of the C9orf72 locus in a large cohort of Chinese samples provides robust evidence that may not be consistent with a single Caucasian founder event. Both the Caucasian and Chinese haplotypes associated with HRE were highly associated with repeat lengths >8 repeats implying that both haplotypes may confer instability of repeat length.
C9orf72基因中的六核苷酸重复序列扩增（HRE）已被确定为白种人群中肌萎缩侧索硬化症（ALS）最常见的突变。我们试图全面评估中国ALS患者中C9orf72的基因和表观遗传变异以及HRE的作用。我们对来自中国的1092例散发性ALS（sALS）患者和1062例对照进行了片段长度和重复引物聚合酶链反应，以确定C9orf72基因内的GGGGCC拷贝数和扩增情况。我们对C9orf72内部及周围的23个单核苷酸多态性进行了单倍型分析。在3例sALS患者（0.3%）中发现了C9orf72 HRE，但在对照受试者中未发现（p = 0.25）。对于2例携带HRE的患者，HRE侧翼的8个单核苷酸多态性的基因型与报道的在白种人群中与ALS强烈相关的单倍型不一致。对于这2例个体，我们发现重复序列上游的CpG岛发生了高甲基化，这一现象在其他sALS患者（p < 10(-8)）或对照中未检测到。对大量中国样本中C9orf72基因座的详细分析提供了有力证据，表明其可能与单一的白种人奠基者事件不一致。与HRE相关的白种人和中国单倍型均与重复长度>8次重复高度相关，这意味着两种单倍型可能都赋予了重复长度的不稳定性。
