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

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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.