title: Novel rare variants in F-box protein 45 (FBXO45) in schizophrenia.
abstract: The ubiquitin ligase F-box protein 45 (FBXO45) is critical for synaptogenesis, neuronal migration, and synaptic transmission. FBXO45 is included in the 3q29 microdeletion region that confers a significant risk for schizophrenia, as shown by rare structural variant studies. Thus, FBXO45 is considered a prominent candidate for mediating schizophrenia pathogenesis. Here, we investigated rare, deleterious single nucleotide variants (SNVs) as well as small insertions and deletions (INDELs) in FBXO45 that may contribute to schizophrenia susceptibility. Using Sanger sequencing, we performed mutation screening in FBXO45 exon regions in 337 schizophrenia patients. Novel missense or nonsense variants were followed up with a genetic association study in an independent sample set of 601 schizophrenia patients and 916 controls, a case report for assessing the clinical consequence of the mutations, a pedigree study for measuring mutation inheritance in the proband's family, bioinformatics analyses for evaluating mutation effect on protein structure and function, and mRNA expression analysis for examining mutation transcriptional influence on FBXO45 expression. One heterozygous, novel, and rare missense mutation (R108C) was identified in a single schizophrenia patient and in his healthy mother. At age 20, this patient was diagnosed with paranoid schizophrenia and carried some clinical features of 3q29 deletion phenotypes, including premorbid IQ decline. With follow-up genotyping, this mutation was not found in either the schizophrenia group (0/601) or the healthy control group (0/916). Bioinformatics analyses predicted that R108C probably pathologically impacted the structure and function of the FBXO45 protein. The relative expression of FBXO45 in SCZ case with R108C mutation was relatively low when compared to 50 schizophrenia patients and 52 healthy controls. The R108C mutation in FBXO45 is a rare variant with a modest effect on schizophrenia risk that may disrupt the structure and function of the FBXO45 protein. Our findings also suggest that FBXO45 may be a new attractive candidate gene for schizophrenia.
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Chenyao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Koide
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shohko
authors.initials: S
authors.lastname: Kunimoto
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Kushima
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Banno
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kawano
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Takasaki
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Jingrui
authors.initials: J
authors.lastname: Xing
authors.affiliation: Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.affiliation: Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: branko@med.nagoya-u.ac.jp.
authors.forename: Branko
authors.initials: B
authors.lastname: Aleksic
authors.affiliation: Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Iidaka
authors.affiliation: Institute of Neuropsychiatry, Seiwa Hospital, Tokyo, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.affiliation: Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
mesh_terms: D000328:Adult; D002460:Cell Line; D004252:DNA Mutational Analysis; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*; D012563:Schizophrenia, Paranoid / Q000235:genetics; D017385:Sequence Homology; D055815:Young Adult
chemical_list: D044783:F-Box Proteins; C503710:FBXO45 protein, human; D012333:RNA, Messenger
keywords: 3q29 microdeletion; FBXO45; Rare mutation; Resequencing; Schizophrenia