1. Synuclein gene alterations in dementia with Lewy bodies
- Author
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Miho Murata, Akiyoshi Kakita, Hiroaki Ohtake, Osamu Onodera, Atsushi Ishikawa, Pornprot Limprasert, Lauren T. Bonner, John Q. Trojanowski, Jiro Idezuka, A. R. La Spada, Shoji Tsuji, Haruhiko Takahashi, James B. Leverenz, Tatsushi Toda, Virginia M.-Y. Lee, Y. Fan, Thomas D. Bird, Ian V.J. Murray, and Debby W. Tsuang
- Subjects
Male ,Cystic Fibrosis ,animal diseases ,DNA Mutational Analysis ,Mice ,chemistry.chemical_compound ,Japan ,Thrombophilia ,Aged, 80 and over ,Genetics ,education.field_of_study ,Parkinson Disease ,Middle Aged ,Penetrance ,Pedigree ,Disease Progression ,alpha-Synuclein ,Female ,Lewy Body Disease ,Washington ,Molecular Sequence Data ,Population ,Mutation, Missense ,Synucleins ,Nerve Tissue Proteins ,Biology ,beta-Synuclein ,Species Specificity ,mental disorders ,medicine ,Animals ,Humans ,Point Mutation ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Allele ,Codon ,education ,Gene ,Aged ,Brain Chemistry ,Alpha-synuclein ,Sequence Homology, Amino Acid ,Dementia with Lewy bodies ,Point mutation ,medicine.disease ,Rats ,nervous system diseases ,Amino Acid Substitution ,nervous system ,chemistry ,Cattle ,Neurology (clinical) ,Beta-synuclein ,Sequence Alignment - Abstract
Objective: To determine whether mutations in the genes for α-synuclein or β-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). Methods: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for α-synuclein and β-synuclein, as α-synuclein alterations cause PD and β-synuclein may modulate α-synuclein aggregation and neurotoxicity. Results: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the β-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the β-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients’ population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H β-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and α-synuclein aggregation without evidence of β-synuclein aggregation. Conclusion: Mutations in the β-synuclein gene may predispose to DLB.
- Published
- 2004
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