Nishiyama Ayumi, Niihori Tetsuya, Warita Hitoshi, Izumi Rumiko, Akiyama Tetsuya, Kato Masaaki, Suzuki Naoki, Aoki Yoko, Aoki Masashi
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Neurobiol Aging. 2017 May;53:194.e1-194.e8. doi: 10.1016/j.neurobiolaging.2017.01.004. Epub 2017 Jan 10.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients. A novel likely pathogenic homozygous variant in ALS2 was identified in 1 patient. In addition, 18 patients harbored 1-3 novel variants of uncertain significance, whereas hexanucleotide repeat expansions in C9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG, and OPTN variants were 32%, 11%, 2%, 2%, 1%, and 1%, respectively. These findings indicate considerable differences in the genetic variations associated with familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted.
肌萎缩侧索硬化症（ALS）是一种成年发病的神经退行性疾病，其特征为运动神经元丧失。我们最近在日本连续的111个家族性ALS家系中确定，超氧化物歧化酶1（SOD1）和融合蛋白（FUS）突变是最常见的病因。为了揭示其余51例家族性ALS患者（45个家系）可能的遗传病因，我们对35个已知的与ALS/运动神经元疾病相关的基因进行了靶向二代测序。在6例患者中鉴定出血管生成素（ANG）、 optineurin（OPTN）、Senataxin（SETX）和TAR DNA结合蛋白（TARDBP）中的已知变异。在1例患者中鉴定出ALS2基因中的一种新的可能致病的纯合变异。此外，18例患者携带1至3种意义未明的新变异，而使用重复引物聚合酶链反应未检测到C9orf72基因中的六核苷酸重复扩增。总体而言，在我们的日本队列中，SOD1、FUS、SETX、TARDBP、ANG和OPTN变异的频率分别为32%、11%、2%、2%、1%和1%。这些发现表明，不同人群中与家族性ALS相关的基因变异存在显著差异。有必要对新变异进行进一步的遗传分析和功能研究。
