title: Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies.
abstract: Disturbances of lipid metabolism have been implicated in psychiatric illnesses. We previously reported an association between the gene for fatty acid binding protein 7 (FABP7) and schizophrenia. Furthermore, we identified and reported several rare non-synonymous polymorphisms of the brain-expressed genes FABP3, FABP5 and FABP7 from schizophrenia and autism spectrum disorder (ASD), diseases known to part share genetic architecture. Here, we conducted further studies to better understand the contribution these genes make to the pathogenesis of schizophrenia and ASD. In postmortem brains, we detected altered mRNA expression levels of FABP5 in schizophrenia, and of FABP7 in ASD and altered FABP5 in peripheral lymphocytes. Using a patient cohort, comprehensive mutation screening identified six missense and two frameshift variants from the three FABP genes. The two frameshift proteins, FABP3 E132fs and FABP7 N80fs, formed cellular aggregates and were unstable when expressed in cultured cells. The four missense mutants with predicted possible damaging outcomes showed no changes in intracellular localization. Examining ligand binding properties, FABP7 S86G and FABP7 V126L lost their preference for docosahexaenoic acid to linoleic acid. Finally, mice deficient in Fabp3, Fabp5 and Fabp7 were evaluated in a systematic behavioral test battery. The Fabp3 knockout (KO) mice showed decreased social memory and novelty seeking, and Fabp7 KO mice displayed hyperactive and anxiety-related phenotypes, while Fabp5 KO mice showed no apparent phenotypes. In conclusion, disturbances in brain-expressed FABPs could represent an underlying disease mechanism in a proportion of schizophrenia and ASD sufferers.
authors.affiliation: Department of Biological Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 112-8610, Japan, Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Shimamoto
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohnishi
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Maekawa
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ohba
authors.affiliation: Division of Applied Biology, Faculty of Textile Science and Technology, Shinshu University, Nagano 386-8567, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Arai
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hisano
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Toyoshima
authors.affiliation: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba 299-0111, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Shirayama
authors.affiliation: Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Aomori 036-8562, Japan and.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Mori
authors.affiliation: Department of Organ Anatomy, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Owada
authors.affiliation: Department of Biological Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 112-8610, Japan.
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan, takeo@brain.riken.jp.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005106:Exploratory Behavior; D000074026:Fatty Acid Binding Protein 3; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C493408:FABP3 protein, human; C493412:FABP5 protein, human; C107608:FABP7 protein, human; C493409:Fabp3 protein, mouse; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D004281:Docosahexaenoic Acids; D019787:Linoleic Acid