C9orf72下游六核苷酸重复区序列变异及其对重复引物PCR解释的影响:一项大型跨国筛选研究

IF 2.5 4区 医学 Q2 CLINICAL NEUROLOGY Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2017-04-03 DOI:10.1080/21678421.2016.1262423
Angelica Nordin, C. Akimoto, Anna Wuolikainen, Helena Alstermark, K. Forsberg, P. Baumann, S. Pinto, M. de Carvalho, A. Hübers, Frida Nordin, A. Ludolph, Jochen H Weishaupt, T. Meyer, T. Grehl, K. Schweikert, Markus Weber, Christian Burkhardt, C. Neuwirth, T. Holmøy, M. Morita, O. Tysnes, M. Benatar, J. Wuu, D. Lange, C. Bisgård, N. Asgari, I. Tarvainen, T. Brännström, P. Andersen
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引用次数: 16

摘要

摘要C9orf72中的一个大GGGGCC重复扩增突变(HREM)是欧洲人群中ALS和FTD最常见的已知原因。先前已经观察到HREM区域下游的序列变化,并认为这是解释RP-PCR数据困难的原因之一。我们的目的是确定这些序列变异在患病率、变异范围和对疾病预后的影响方面的特性。我们筛选了一个多国队列(n = 6981),并鉴定出具有偏差RP-PCR曲线的样品。随后对异常样本进行测序,以确定序列变化。我们的结果表明,在美国和欧洲的队列中(n = 6508)10.7%携带HREM,3%有序列变异,而在日本队列中没有观察到HREM或序列变异(n = 473)。HREM等位基因的序列变异更为常见;然而,某些群体特异性变异与非扩增等位基因相关。总之,我们确定了38个不同的序列变体,大多数位于前50个 HREM区域下游的bp。此外,发现HREM的存在与较低的发病年龄和较短的疾病生存期有关,而序列变异与这些参数没有任何相关性。
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Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study
Abstract A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele.In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.
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来源期刊
CiteScore
5.40
自引率
10.70%
发文量
64
期刊介绍: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration is an exciting new initiative. It represents a timely expansion of the journal Amyotrophic Lateral Sclerosis in response to the clinical, imaging pathological and genetic overlap between ALS and frontotemporal dementia. The expanded journal provides outstanding coverage of research in a wide range of issues related to motor neuron diseases, especially ALS (Lou Gehrig’s disease) and cognitive decline associated with frontotemporal degeneration. The journal also covers related disorders of the neuroaxis when relevant to these core conditions.
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