Gene analysis of amyotrophic lateral sclerosis/parkinsonism-dementia complex, Kii, Japan

目的：明确日本纪井半岛肌萎缩性侧索硬化症/帕金森病-痴呆复合体（ALS/PDC）的遗传背景。方法：我们对3例病理诊断为Kii ALS/PDC的患者进行了扩展突变分析。对19个基因进行直接测序分析，包括肌萎缩性侧索硬化症(ALS)/额颞叶变性（FTLD）相关基因（SOD2、SOD3、ALS2 alsin、SMN1、PGRN、ANG、VEGF、VCP、VAPB、DCTN1、CHMP2B和TARDBP）、tau病相关基因（GSK3β）和帕金森病相关基因（α -突触核蛋白、LRRK2、parkin、DJ-1、PINK1和ATP13A2）。基因剂量分析筛选MAPT、α -突触核蛋白、TARDBP、GSK3β和parkin。结果：19个基因未发现突变。我们在所有3例患者中发现了一个纯合的非同义SNP（ALS2 alsin V368M）。MAPT、α -突触核蛋白、TARDBP、GSK3β、pakin基因用量正常。结论：本研究结果与先前对MAPT和SOD1突变的阴性研究一起，进一步阐明了与ALS、FTLD、帕金森病、突触核蛋白病和tau病相关的主要致病或易感基因在所有外显子、外显子内含子边界或某些重排中缺乏致病突变。然而，家族聚集性和缺乏任何环境因素提示Kii ALS/PDC是由其他尚未确定的遗传因素引起的。

Objectives : To clarify the genetic background of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the Kii peninsula, Japan (KiiALS/PDC). Methods : We performed extended mutation analyses of three patients with pathologically diagnosed Kii ALS/PDC. Direct sequencing analyses were performed in 19 genes, including amyotrophic lateral sclerosis(ALS)/frontotemporal lobar degeneration (FTLD)-related genes(SOD2, SOD3, ALS2 alsin, SMN1, PGRN, ANG, VEGF, VCP, VAPB, DCTN1, CHMP2B, and TARDBP), tauopathy-related gene (GSK3β), and parkinsonism-related genes(alpha-synuclein, LRRK2, parkin, DJ-1, PINK1, and ATP13A2). Gene dosage analyses were conducted in screening of MAPT, alpha-synucleln, TARDBP,GSK3β, and parkin. Results : We found no mutation in the 19 genes. We found a homozygous non-synonymous SNP(ALS2 alsin V368M) shared in all the three patients. Gene dosage was normal in MAPT, alpha-synuclein, TARDBP, GSK3β, and pakin.Conclusions : The present findings, together with a previous negative study on MAPT and SOD1 mutation, further elucidated the lack of causative mutation in all exons, exon intron boundaries, or some rearrangements of the reported major causative or susceptible genes related to ALS, FTLD, parkinsonism, synucleinopathy, and tauopathy. However, the familial aggregation and lack of any environment factors suggest that Kii ALS/PDC is caused by other yet unidentified genetic factors.