title: FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease.
abstract: Mutations in the F-box only protein 7 gene (FBXO7), the substrate-specifying subunit of SCF E3 ubiquitin ligase complex, cause Parkinson's disease (PD)-15 (PARK15). To identify new variants, we sequenced FBXO7 cDNA in 80 Taiwanese early onset PD patients (age at onset ≤ 50) and only two known variants, Y52C (c.155A>G) and M115I (c.345G>A), were found. To assess the association of Y52C and M115I with the risk of PD, we conducted a case-control study in a cohort of PD and ethnically matched controls. There was a nominal difference in the Y52C G allele frequency between PD and controls (p = 0.045). After combining data from China [1], significant difference in the Y52C G allele frequency between PD and controls (p = 0.012) and significant association of G allele with decreased PD risk (p = 0.017) can be demonstrated. Upon expressing EGFP-tagged Cys52 FBXO7 in cells, a significantly reduced rate of FBXO7 protein decay was observed when compared with cells expressing Tyr52 FBXO7. In silico modeling of Cys52 exhibited a more stable feature than Tyr52. In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced. Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination, which may be responsible for the reduced TRAF2 expression in Cys52 cells. After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth. We therefore hypothesize that Cys52 variant of FBXO7 may contribute to reduced PD susceptibility in Chinese.
authors.affiliation: Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
authors.forename: I-Cheng
authors.initials: IC
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsueh-Fen
authors.initials: HF
authors.lastname: Juan
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Ying-Lin
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lee
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chi-Mei
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D044783:F-Box Proteins; C489149:FBXO7 protein, human; D047992:TNF Receptor-Associated Factor 2; D015655:1-Methyl-4-phenylpyridinium