TY - JOUR
T1 - Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine
AU - Nakazawa, Takanobu
AU - Kikuchi, Masataka
AU - Ishikawa, Mitsuru
AU - Yamamori, Hidenaga
AU - Nagayasu, Kazuki
AU - Matsumoto, Takuya
AU - Fujimoto, Michiko
AU - Yasuda, Yuka
AU - Fujiwara, Mikiya
AU - Okada, Shota
AU - Matsumura, Kensuke
AU - Kasai, Atsushi
AU - Hayata-Takano, Atsuko
AU - Shintani, Norihito
AU - Numata, Shusuke
AU - Takuma, Kazuhiro
AU - Akamatsu, Wado
AU - Okano, Hideyuki
AU - Nakaya, Akihiro
AU - Hashimoto, Hitoshi
AU - Hashimoto, Ryota
N1 - Publisher Copyright:
© 2016 The Authors
PY - 2017/3/1
Y1 - 2017/3/1
N2 - Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.
AB - Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.
KW - Clozapine
KW - Drug response
KW - Monozygotic twins
KW - Treatment-resistant schizophrenia
KW - iPS cell
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UR - http://www.scopus.com/inward/citedby.url?scp=85006025218&partnerID=8YFLogxK
U2 - 10.1016/j.schres.2016.10.012
DO - 10.1016/j.schres.2016.10.012
M3 - Article
C2 - 28277309
AN - SCOPUS:85006025218
SN - 0920-9964
VL - 181
SP - 75
EP - 82
JO - Schizophrenia Research
JF - Schizophrenia Research
ER -