Tomiyama Hiroyuki, Kokubo Yasumasa, Sasaki Ryogen, Li Yuanzhe, Imamichi Yoko, Funayama Manabu, Mizuno Yoshikuni, Hattori Nobutaka, Kuzuhara Shigeki
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
Mov Disord. 2008 Dec 15;23(16):2344-8. doi: 10.1002/mds.22262.
To clarify the genetic background of amyotrophic lateral sclerosis (ALS)/parkinsonism-dementia complex (PDC) of the Kii peninsula, Japan (Kii ALS/PDC), we performed extended mutation analyses of three patients with pathologically diagnosed Kii ALS/PDC. Direct sequencing analyses were performed in 19 genes, including ALS/frontotemporal lobar degeneration (FTLD)-related genes (SOD2, SOD3, ALS2/alsin, SMN1, PGRN, ANG, VEGF, VCP, VAPB, DCTN1, CHMP2B, and TARDBP or TDP-43), tauopathy-related gene (GSK3beta), and parkinsonism-related genes (alpha-synuclein, LRRK2, parkin, DJ-1, PINK1, and ATP13A2). Gene dosage analyses were conducted in screening of MAPT, alpha-synuclein, TDP-43 (or TARDBP), GSK3beta, and parkin. We found no mutation in the 19 genes. We found a homozygous nonsynonymous SNP (ALS2/alsin V368M) shared by all the three patients. Gene dosage was normal in MAPT, alpha-synuclein, TDP-43, GSK3beta, and parkin. The present findings, together with a previous negative study on MAPT and SOD1 mutation, further elucidated the lack of causative mutations in all exons, exon-intron boundaries, or some rearrangements of the reported major causative or susceptible genes related to ALS, FTLD, parkinsonism, synucleinopathy, TDP-43 proteinopathy, 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.
为阐明日本纪伊半岛肌萎缩侧索硬化症（ALS）/帕金森病痴呆综合征（PDC）（纪伊ALS/PDC）的遗传背景，我们对3例经病理诊断为纪伊ALS/PDC的患者进行了扩展突变分析。对19个基因进行了直接测序分析，包括与ALS/额颞叶痴呆（FTLD）相关的基因（SOD2、SOD3、ALS2/alsin、SMN1、PGRN、ANG、VEGF、VCP、VAPB、DCTN1、CHMP2B以及TARDBP或TDP-43）、tau蛋白病相关基因（GSK3β）以及帕金森病相关基因（α-突触核蛋白、LRRK2、帕金森病蛋白、DJ-1、PINK1和ATP13A2）。在筛选MAPT、α-突触核蛋白、TDP-43（或TARDBP）、GSK3β和帕金森病蛋白时进行了基因剂量分析。我们在这19个基因中未发现突变。我们发现所有3例患者均共享一个纯合非同义单核苷酸多态性（ALS2/alsin V368M）。MAPT、α-突触核蛋白、TDP-43、GSK3β和帕金森病蛋白的基因剂量均正常。目前的研究结果，连同之前关于MAPT和SOD1突变的阴性研究，进一步阐明了在所有外显子、外显子-内含子边界或与ALS、FTLD、帕金森病、突触核蛋白病、TDP-43蛋白病和tau蛋白病相关的已报道主要致病或易感基因的某些重排中不存在致病突变。然而，家族聚集性以及缺乏任何环境因素表明，纪伊ALS/PDC是由其他尚未确定的遗传因素引起的。
