DNA Methylation and Gene Expression of Matrix Metalloproteinase 9 Gene in Deficit and Non-deficit Schizophrenia.

Ju Gao,Xiangrong Zhang,Xiaobin Zhang,Xiaotang Feng,Hongwei Yi,Miao Yu,Xiaowei Tang,Weiwei Sha,Xiang Wang

doi:10.3389/fgene.2018.00646

Abstract

The biological pathology of deficit schizophrenia (DS) remains unclear. Matrix metalloproteinase 9 (MMP9) might be associated with neural plasticity and glutamate regulation, involved in schizophrenia pathogenesis. This study explores gene expression and DNA methylation of MMP9 in peripheral blood mononuclear cells (PBMCs) and their relationship with clinical symptoms in DS and non-deficit schizophrenia (NDS). Pyrosequencing was used to determine DNA methylation at CpG sites in exon 4 and exon 5 of MMP9 in 51 DS patients, 53 NDS patients and 50 healthy subjects (HC). RT-qPCR was used to detect MMP9 expression. Clinical symptoms were assessed by BPRS, SANS and SAPS scales. MMP9 expression in PBMCs was significantly higher in DS than NDS and HC subjects. Compared to NDS patients, DS patients had significantly lower DNA methylation at individual CpG sites in exon 4 and exon 5 of MMP9. Correlation analysis showed that DNA methylation in exon 4 was negatively correlated with gene expression in DS group. Positive correlation was found between MMP9 expression and negative symptoms in total schizophrenic patients. The social amotivation factor of SANS and negative syndrome of BPRS was negatively correlated with DNA methylation of CpG5-1 in DS patients but not in NDS patients. DS patients showed a specific abnormality of peripheral MMP9 expression and DNA methylation, indicating a pathological mechanism underlying DS as a specific subgroup of schizophrenia.

Highlights

Schizophrenia is a severe psychiatric disorder with impairment of perception, thought, emotion and behavior, resulting in profoundly impaired social function
Consistent with Brief Psychiatric Rating Scale (BPRS) measurement, SANS scores were higher in Deficit schizophrenia (DS) group than non-deficit schizophrenia (NDS) group but no significant differences seen in Scale for the Assessment of Positive Symptoms (SAPS) scores
The present study demonstrated that the epigenetic pattern and gene expression of Matrix metalloproteinase 9 (MMP9) of peripheral blood mononuclear cells was different among DS, NDS, and healthy subjects (HC) groups

Summary

Introduction

Schizophrenia is a severe psychiatric disorder with impairment of perception, thought, emotion and behavior, resulting in profoundly impaired social function. Negative symptoms are characterized by an absence or reduction of affective, social and behavioral expression, which are regarded as important predictors of treatment response and prognosis (Foussias et al, 2011). The MMP9 Methylation in Deficit Schizophrenia heterogeneity of negative symptoms, primary or secondary symptoms, could lead to the substantial differences in clinical outcome of antipsychotic response and disease prognosis (Aleman et al, 2016). Deficit schizophrenia (DS), proposed by Carpenter et al (1988), characterizes patients with primary and permanent negative symptoms including restricted affect, diminished emotional range, poverty of speech, curbing of interests, diminished sense of purpose and diminished social drive (Carpenter et al, 1988; Kirkpatrick et al, 1989, 2001). The research on DS might help to understand the etiology of negative symptoms and prediction biomarkers for the long-term prognosis of patients with schizophrenia

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