Novel rare variants in F-box protein 45 (FBXO45) in schizophrenia

Chenyao Wang, Takayoshi Koide, Hiroki Kimura, Shohko Kunimoto, Akira Yoshimi, Yukako Nakamura, Itaru Kushima, Masahiro Banno, Naoko Kawano, Yuto Takasaki, Jingrui Xing, Yukihiro Noda, Akihiro Mouri, Branko Aleksic, Masashi Ikeda, Takashi Okada, Tetsuya Iidaka, Toshiya Inada, Nakao Iwata, Norio Ozaki

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13 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)149-156
Number of pages8
JournalSchizophrenia Research
Issue number1-3
Publication statusPublished - 08-2014

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Biological Psychiatry


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