Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype.
Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype.
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DOI：
10.3389/fnagi.2021.658226
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发表时间：
2021
影响因子：
4.8
通讯作者：
Akkari PA
中科院分区：
文献类型：
--
作者：
Theunissen F;Anderton RS;Mastaglia FL;Flynn LL;Winter SJ;James I;Bedlack R;Hodgetts S;Fletcher S;Wilton SD;Laing NG;MacShane M;Needham M;Saunders A;Mackay-Sim A;Melamed Z;Ravits J;Cleveland DW;Akkari PA
有一个关键需要建立遗传标记，解释复杂的表型和致病性的ALS。本研究确定了Stathmin-2基因的多态性，并研究了其与散发性ALS（sALS）疾病风险、发病年龄和生存时间的相关性。采用PCR、桑格测序和高通量毛细管电泳技术对候选CA重复序列进行系统分析。使用RT-PCR在患者嗅神经球衍生（ONS）细胞中研究Stathmin-2表达，并在激光捕获的脊髓运动神经元中进行RNA测序。在一项对北美sALS联合队列（n = 321）和人群对照组（n = 332）的病例对照分析中，长/长CA基因型与疾病风险显著相关（p = 0.042），当一个等位基因是24 CA重复时（p = 0.0023）最强。此外，较长的CA等位基因长度与较早的发病年龄（p = 0.039）和较短的生存期在延髓发病的情况下（p = 0.006）。在澳大利亚纵向sALS队列（n = 67），ALS功能评定量表评分显着较低的长/长基因型（p = 0.034）的运营商。在散发患者ONS细胞中Stathmin-2 mRNA表达降低。此外，sALS患者和对照组在激光捕获的脊髓运动神经元中根据CA基因型表现出Stathmin-2 mRNA的可变表达。我们报告了Stathmin-2中一种新的非编码CA重复序列，该序列与sALS疾病风险相关，并具有疾病修饰作用。这种变异作为疾病标志物和临床试验中队列富集工具的潜在价值值得进一步研究。
There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration. The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons. In a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons. We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.
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DOI：
10.1002/neu.20295
发表时间：
2006-09-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Morii, Hiroshi;Shiraishi-Yamaguchi, Yoko;Mori, Nozomu
通讯作者：
Mori, Nozomu
DOI：
10.1007/978-1-62703-574-3_10
发表时间：
2013-01-01
期刊：
NEURAL PROGENITOR CELLS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Feron, Francois;Perry, Chris;Mackay-Sim, Alan
通讯作者：
Mackay-Sim, Alan
影响因子：
4
作者：
Cleary, John Douglas;Ranum, Laura P. W.
通讯作者：
Ranum, Laura P. W.
影响因子：
4.4
作者：
Blasco, Helene;Vourc'h, Patrick;Corcia, Philippe
通讯作者：
Corcia, Philippe
影响因子：
4.3
作者：
Gorecki, Anastazja M.;Preskey, Leah;Anderton, Ryan S.
通讯作者：
Anderton, Ryan S.