title: Beta-synuclein gene alterations in dementia with Lewy bodies.
abstract: OBJECTIVE
  To determine whether mutations in the genes for alpha-synuclein or beta-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 alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-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 beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-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 beta-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 alpha-synuclein aggregation without evidence of beta-synuclein aggregation.
  
  
  CONCLUSIONS
  Mutations in the beta-synuclein gene may predispose to DLB.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ohtake
authors.forename: P
authors.initials: P
authors.lastname: Limprasert
authors.forename: Y
authors.initials: Y
authors.lastname: Fan
authors.forename: O
authors.initials: O
authors.lastname: Onodera
authors.forename: A
authors.initials: A
authors.lastname: Kakita
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: L T
authors.initials: LT
authors.lastname: Bonner
authors.forename: D W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: I V J
authors.initials: IV
authors.lastname: Murray
authors.forename: V M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: A
authors.initials: A
authors.lastname: Ishikawa
authors.forename: J
authors.initials: J
authors.lastname: Idezuka
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: T
authors.initials: T
authors.lastname: Toda
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
authors.forename: J B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
authors.forename: A R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001923:Brain Chemistry; D002417:Cattle; D003062:Codon / Q000235:genetics; D003550:Cystic Fibrosis / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan / Q000453:epidemiology; D020961:Lewy Body Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D051843:Synucleins; D019851:Thrombophilia / Q000235:genetics; D014861:Washington / Q000453:epidemiology; D051844:alpha-Synuclein; D051846:beta-Synuclein
chemical_list: D003062:Codon; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497607:SNCB protein, human; C497605:Snca protein, mouse; C497606:Snca protein, rat; C497608:Sncb protein, mouse; C497609:Sncb protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein