NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis
NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis
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DOI：
10.1093/hmg/dds064
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发表时间：
2012-06-01
影响因子：
3.5
通讯作者：
van den Berg, Leonard H.
中科院分区：
文献类型：
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作者：
Blauw, Hylke M.;van Rheenen, Wouter;van den Berg, Leonard H.
NIPA 1的突变导致遗传性痉挛性截瘫6型，这是一种以（上）运动神经元表型为特征的神经退行性疾病。NIPA 1的缺失与肌萎缩侧索硬化症（ALS）的易感性增加有关。然而，NIPA 1遗传变异在ALS易感性和病程中的确切作用尚不清楚。我们对NIPA 1的整个编码序列进行了测序，并对位于NIPA 1第一外显子的多聚丙氨酸重复序列进行了基因分型。共有2292名ALS患者和2777名来自三个独立的欧洲人群的对照被纳入。我们确定了两个对NIPA 1蛋白功能具有潜在破坏作用的序列变体。在ALS患者中发现了这两种变体;在对照组中没有发现破坏性变体。其次，我们发现olong'多聚丙氨酸重复等位基因对疾病易感性有显著影响：比值比1.71，P 1.6 10（4）。我们的分析还显示olong'等位基因对患者生存率[风险比（HR）1.60，P 4.2 10（4）]和症状发作时的年龄（HR 1.37，P 4.6 10（3））有显著影响。在携带Oong '等位基因的患者中，中位生存期比非正常基因型患者短3个月，症状出现时间提前3.6年。我们的数据表明，NIPA 1多聚丙氨酸重复扩增是ALS的常见危险因素，并调节疾病进程。
Mutations in NIPA1 cause Hereditary Spastic Paraplegia type 6, a neurodegenerative disease characterized by an (upper) motor neuron phenotype. Deletions of NIPA1 have been associated with a higher susceptibility to amyotrophic lateral sclerosis (ALS). The exact role of genetic variation in NIPA1 in ALS susceptibility and disease course is, however, not known. We sequenced the entire coding sequence of NIPA1 and genotyped a polyalanine repeat located in the first exon of NIPA1. A total of 2292 ALS patients and 2777 controls from three independent European populations were included. We identified two sequence variants that have a potentially damaging effect on NIPA1 protein function. Both variants were identified in ALS patients; no damaging variants were found in controls. Secondly, we found a significant effect of olong' polyalanine repeat alleles on disease susceptibility: odds ratio 1.71, P 1.6 10(4). Our analyses also revealed a significant effect of olong' alleles on patient survival [hazard ratio (HR) 1.60, P 4.2 10(4)] and on the age at onset of symptoms (HR 1.37, P 4.6 10(3)). In patients carrying olong' alleles, median survival was 3 months shorter than patients with onormal' genotypes and onset of symptoms occurred 3.6 years earlier. Our data show that NIPA1 polyalanine repeat expansions are a common risk factor for ALS and modulate disease course.