Evidence towards RNA Binding Motif (RNP1, RRM) Protein 3 (RBM3) as a Potential Biomarker of Lithium Response in Bipolar Disorder Patients
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Lithium has been used for more than six decades for the management of bipolar disorder (BD). In a previous transcriptomic study, we showed that patients affected by either BD or cluster headache, both disorders characterized by circadian disturbances and response to lithium in a subgroup of patients, have higher expression of the RNA binding motif (RNP1, RRM) protein 3 (RBM3) gene compared to controls. To investigate whether RBM3 could represent a biomarker of lithium response, we screened raw microarray expression data from lymphoblastoid cell lines (LCLs) derived from 20 BD patients, responders or non-responders to lithium. RBM3 was the most significantly differentially expressed gene in the list, being overexpressed in responders compared to non-responders (fold change = 2.0; p = 1.5 × 10−16). We therefore sought to validate the microarray finding by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and explore whether RBM3 expression was modulated by lithium treatment in vitro in LCLs as well as in human-derived neural progenitor cells (NPCs). Our findings confirmed the higher expression of RBM3 in responders compared to non-responders (fold change = 3.78; p = 0.0002). Lithium did not change RBM3 expression in LCLs in any of the groups, but it increased its expression in NPCs. While preliminary, our data suggest that higher levels of RBM3 might be required for better lithium response and that the expression of this gene could be modulated by lithium in a tissue-specific manner.
KeywordsCircadian rhythm Gene expression Lithium response Neuroprotection Bipolar disorder Mood stabilizers
RNA binding motif (RNP1, RRM) protein 3
Lymphoblastoid cell lines
Quantitative reverse transcription polymerase chain reaction
Neural progenitor cells
Differentially expressed genes
Induced pluripotent stem cell
Comparative Ct method
False discovery rate
- Nr1d1, NR1D1
Nuclear receptor subfamily 1 group D member 1
Glycogen synthase kinase 3 beta
Insulin-like growth factor 1
Peripheral blood mononuclear cells
This work was partially funded by a grant from Regione Autonoma della Sardegna (RAS), L7/2007, 2013, call 2013, grant number: 79506. Moreover, the authors wish to thank the patients and their families for participating in this study.
Compliance with Ethical Standards
Our study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans, was approved by the ethics committee of the Teaching Hospital of Cagliari (Italy), and written informed consent was obtained from all participants.
Conflict of Interest
The authors declare that they have no conflicts of interest.
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