TY - JOUR
T1 - Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies
AU - Shimamoto, Chie
AU - Ohnishi, Tetsuo
AU - Maekawa, Motoko
AU - Watanabe, Akiko
AU - Ohba, Hisako
AU - Arai, Ryoichi
AU - Iwayama, Yoshimi
AU - Hisano, Yasuko
AU - Toyota, Tomoko
AU - Toyoshima, Manabu
AU - Suzuki, Katsuaki
AU - Shirayama, Yukihiko
AU - Nakamura, Kazuhiko
AU - Mori, Norio
AU - Owada, Yuji
AU - Kobayashi, Tetsuyuki
AU - Yoshikawa, Takeo
N1 - Funding Information:
This study was supported in part by Grants-in-Aid for Scientific Research (T.Y.) and by Grant-in-Aid for Scientific Research on Innovative Areas (T.Y.), from the Japan Society for the Promotion of Science (JSPS), Japan. In addition, this study was supported by RIKEN Brain Science Institute Funds (T.Y.), and a part of this study is the result of the ‘Development of biomarker candidates for social behavior’ (T.Y.) and ‘Integrated research on neuropsychiatric disorders’ projects (N.M.), carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Funding to pay the Open Access publication charges for this article was provided by RIKEN BSI funds.
Publisher Copyright:
© The Author 2014. Published by Oxford University Press.
PY - 2014/12/15
Y1 - 2014/12/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddu369
DO - 10.1093/hmg/ddu369
M3 - Article
C2 - 25027319
AN - SCOPUS:84920270519
VL - 23
SP - 6495
EP - 6511
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 24
ER -