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Mutations for Gaucher Disease Confer High Susceptibility to Parkinson Disease
Jun Mitsui, MD;
Ikuko Mizuta, MD, PhD;
Atsushi Toyoda, PhD;
Ryo Ashida, BS;
Yuji Takahashi, MD, PhD;
Jun Goto, MD, PhD;
Yoko Fukuda, PhD;
Hidetoshi Date, PhD;
Atsushi Iwata, MD, PhD;
Mitsutoshi Yamamoto, MD, PhD;
Nobutaka Hattori, MD, PhD;
Miho Murata, MD, PhD;
Tatsushi Toda, MD, PhD;
Shoji Tsuji, MD, PhD
Arch Neurol. 2009;66(5):571-576.
Background Increased frequency of pathogenic variants in GBA, the causative gene for Gaucher disease, has been suggested to be associated with Parkinson disease (PD).
Objectives To conduct comprehensive resequencing of GBA to identify all sequence variants and to investigate the association of these variants with PD.
Design Case-control study.
Setting Multicenter university-based study.
Participants Five hundred thirty-four patients with PD, 34 families in which multiple patients with PD are present, and 544 control subjects.
Main Outcome Measures Disease status and GBA variations.
Results Comprehensive resequencing of GBA in 534 patients with PD and 544 controls revealed 27 sequence variants: 11 pathogenic variants associated with Gaucher disease, 11 nonsynonymous variants not associated with Gaucher disease, and 5 synonymous variants. Fifty patients with PD (9.4%) had 1 of the 11 pathogenic variants in the heterozygous state, whereas only 2 controls (0.37%) had such variants (odds ratio, 28.0). Among the pathogenic variants, R120W and L444P/RecNciI were highly prevalent, and each showed a significant association with PD. Furthermore, other rare pathogenic variants were found in 13 patients with PD but not in the controls, further confirming the role of these rare variants in the susceptibility to PD. Patients with PD carrying pathogenic variants were significantly younger than those not carrying them. In addition, concordance of PD states and pathogenic variants was observed in 8 multiplex families with PD.
Conclusion Heterozygous pathogenic variants in GBA confer a high risk for sporadic PD, even for familial clustering, and are associated with significantly earlier age at onset of disease.
Author Affiliations: Departments of Neurology, University of Tokyo Graduate School of Medicine (Drs Mitsui, Takahashi, Goto, Fukuda, Date, Iwata, and Tsuji), Juntendo University School of Medicine (Dr Hattori), and Musashi Hospital, National Center of Neurology and Psychiatry (Dr Murata), Tokyo, and Kagawa Prefectural Central Hospital, Takamatsu (Dr Yamamoto); Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka (Drs Mizuta and Toda and Mr Ashida); and Comparative Genomics Laboratory, National Institute of Genetics, Shizuoka (Dr Toyoda), Japan. Dr Murata is now with the National Center of Neurology and Psychiatry, Tokyo.
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