Department of Neurology, University Medical Center Utrecht, Heidelberglaan , Utrecht, The Netherlands
Hum Mol Genet. 2012 Jun 1;21(11):2497-502. doi: 10.1093/hmg/dds064. Epub 2012 Feb 28.
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 'long' polyalanine repeat alleles on disease susceptibility: odds ratio = 1.71, P = 1.6 × 10(-4). Our analyses also revealed a significant effect of 'long' 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 'long' alleles, median survival was 3 months shorter than patients with 'normal' 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.
NIPA1 基因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。NIPA1 的缺失与肌萎缩侧索硬化症（ALS）的易感性增加有关。然而，NIPA1 基因变异在 ALS 易感性和疾病进程中的确切作用尚不清楚。我们对 NIPA1 的整个编码序列进行了测序，并对位于 NIPA1 第一外显子的多聚丙氨酸重复序列进行了基因分型。共有来自三个独立欧洲人群的 2292 名 ALS 患者和 2777 名对照者参与了本研究。我们鉴定出了两个可能对 NIPA1 蛋白功能具有潜在破坏性影响的序列变异体。这两种变异体都在 ALS 患者中被发现；在对照组中没有发现有害的变异体。其次，我们发现“长”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)。我们的分析还揭示了“长”等位基因对患者生存的显著影响[风险比（HR）=1.60，P=4.2×10(-4)]和对症状发病年龄的显著影响（HR=1.37，P=4.6×10(-3))。在携带“长”等位基因的患者中，中位生存期比具有“正常”基因型的患者短 3 个月，且症状发作时间提前 3.6 年。我们的数据表明，NIPA1 多聚丙氨酸重复扩展是 ALS 的常见危险因素，并调节疾病进程。
