Rare mutations and hypermethylation of the ARC gene associated with schizophrenia

Yang An Chuang, Tsung Ming Hu, Chia Hsiang Chen, Shih Hsin Hsu, Hsin Yao Tsai, Min Chih Cheng*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

17 Scopus citations

Abstract

Activity-regulated cytoskeleton-associated protein (ARC), which interacts with the N-methyl-D-aspartate receptor (NMDAR) complex, is a critical effector molecule downstream of multiple neuronal signaling pathways. Dysregulation of the ARC/NMDAR complex can disrupt learning, memory, and normal brain functions. This study examined the role of ARC in susceptibility to schizophrenia. We used a resequencing strategy to identify the variants of ARC in 1078 subjects, including patients with schizophrenia and normal controls. We identified 16 known SNPs and 27 rare mutations. SNP-based analysis showed no association of ARC with schizophrenia. In addition, the rare mutations did not increase the burden in patients compared with controls. However, one patient-specific allele in the putative ARC promoter region and seven patient-specific mutants in ARC exon regions significantly reduced the reporter gene activity compared with ARC wild-type. Methylation of a putative ARC promoter attenuated reporter activity in vitro, suggesting that ARC expression is regulated by DNA methylation. Pyrosequencing revealed eight hypermethylated CpG sites in the putative ARC promoter region in 64 schizophrenic patients compared with 63 controls. Taken together, our results suggest that both rare variants and epigenetic regulation of ARC contribute to the pathogenesis of schizophrenia in some patients.

Original languageEnglish
Pages (from-to)106-113
Number of pages8
JournalSchizophrenia Research
Volume176
Issue number2-3
DOIs
StatePublished - 01 10 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 Elsevier B.V.

Keywords

  • ARC
  • DNA methylation
  • Rare mutation
  • Schizophrenia

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