title: Mutation analyses in amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula, Japan.
abstract: 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.
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomiyama
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Ryogen
authors.initials: R
authors.lastname: Sasaki
authors.forename: Yuanzhe
authors.initials: Y
authors.lastname: Li
authors.forename: Yoko
authors.initials: Y
authors.lastname: Imamichi
authors.forename: Manabu
authors.initials: M
authors.lastname: Funayama
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuzuhara