title: Rare mutations and hypermethylation of the ARC gene associated with schizophrenia.
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.
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Yang-An
authors.initials: YA
authors.lastname: Chuang
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Hu
authors.affiliation: Department of Psychiatry, Chang Gung Memorial Hospital at Linkou and Department and Graduate School of Biomedical Sciences Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Hsu
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Hsin-Yao
authors.initials: HY
authors.lastname: Tsai
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan; Center for General Education, St. Mary's Junior College of Medicine, Nursing and Management, Yilan County, Taiwan. Electronic address: uncle055@yahoo.com.
authors.forename: Min-Chih
authors.initials: MC
authors.lastname: Cheng
mesh_terms: D044466:Asian People / Q000235:genetics; D045744:Cell Line, Tumor; D018899:CpG Islands; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D013624:Taiwan
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein
keywords: ARC; DNA methylation; Rare mutation; Schizophrenia