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ß-Synuclein gene alterations in dementia with Lewy bodies

From the Department of Neurology (Drs. Ohtake and Onodera), Resource Branch for Brain Disease Research (Drs. Onodera and Kakita) & Pathology (Drs. Kakita and Takahashi), Brain Research Institute, Niigata University, Niigata, Japan; Departments of Laboratory Medicine (Drs. Limprasert, Fan, and La Spada), Psychiatry & Behavioral Sciences (Drs. Bonner, Tsuang, and Leverenz), Neurology (Drs. Bird and La Spada), and Medicine (Division of Medical Genetics) (Drs. Bird and La Spada), University of Washington Medical Center, Seattle; Department of Veteran Affairs, Mental Illness Research, Education, and Clinical Center (Drs. Bonner, Tsuang, and Leverenz), Geriatric Research, Education, and Clinical Center (Drs. Bird and Leverenz), and Parkinson Disease Research, Education, and Clinical Center (Dr. Leverenz), Seattle; Center for Neurodegenerative Disease Research in the Department of Pathology and Laboratory Medicine (Drs. Murray, Lee, and Trojanowski) & Institute on Aging (Dr. Trojanowski), University of Pennsylvania, Philadelphia; Agano Hospital (Dr. Ishikawa), Yasuda, Japan; Department of Neurology (Dr. Idezuka), Ojiya Sakura Hospital, Ojiya, Japan; Department of Neurology (Drs. Murata and Tsuji), University of Tokyo, Japan; and Division of Functional Genomics (Dr. Toda), Department of Post-Genomics and Diseases, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.

Address correspondence and reprint requests to Dr. Albert R. La Spada, Department of Laboratory Medicine, University of Washington Medical Center, Box 357110, Room NW 120, Seattle, WA 98195-7110; e-mail: laspada{at}u.washington.edu

Objective: To determine whether mutations in the genes for -synuclein or ß-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 -synuclein and ß-synuclein, as -synuclein alterations cause PD and ß-synuclein may modulate -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 ß-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the ß-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 ß-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 -synuclein aggregation without evidence of ß-synuclein aggregation.

Conclusion: Mutations in the ß-synuclein gene may predispose to DLB.

Received February 5, 2004. Accepted in final form May 21, 2004.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 14 issue to find the title link for this article.

See also page 770

*These authors contributed equally to this work.

Dr. Limprasert’s present address: Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.

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