Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia.
Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.
Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba,Tsukuba, Ibaraki, Japan.
Minori
M
Koga
Hiroki
H
Ishiguro
Saori
S
Yazaki
Yasue
Y
Horiuchi
Makoto
M
Arai
Kazuhiro
K
Niizato
Shuji
S
Iritani
Masanari
M
Itokawa
Toshiya
T
Inada
Nakao
N
Iwata
Norio
N
Ozaki
Hiroshi
H
Ujike
Hiroshi
H
Kunugi
Tsukasa
T
Sasaki
Makoto
M
Takahashi
Yuichiro
Y
Watanabe
Toshiyuki
T
Someya
Akiyoshi
A
Kakita
Hitoshi
H
Takahashi
Hiroyuki
H
Nawa
Christian
C
Muchardt
Moshe
M
Yaniv
Tadao
T
Arinami
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People; D016022:Case-Control Studies; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport; D011619:Psychotropic Drugs / Q000008:administration & dosage; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C497837:ARID1B protein, human; D004268:DNA-Binding Proteins; D011619:Psychotropic Drugs; C084011:SMARCA2 protein, human; D014157:Transcription Factors