Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder.
BACKGROUND
We have previously reported linkage of markers on chromosome 1q22 to schizophrenia, a finding supported by several independent studies. Within this linkage region, we have identified significant linkage disequilibrium between schizophrenia and markers within the gene for carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON). Prior sequencing of the ten exons of CAPON failed to reveal a coding mutation associated with illness.


RESULTS
We screened a human fetal brain cDNA library and identified a new isoform of CAPON that consists of the terminal two exons of the gene, and verified the expression of the predicted corresponding protein in human dorsolateral prefrontal cortex (DLPFC). We examined the expression levels of both the ten-exon CAPON transcript and this new isoform in postmortem brain samples from the Stanley Array Collection. Quantitative real-time PCR analysis of RNA from the DLPFC in 105 individuals (35 with schizophrenia, 35 with bipolar disorder, and 35 psychiatrically normal controls) revealed significantly (p < 0.005) increased expression of the new isoform in both schizophrenia and bipolar disorder. Furthermore, this increased expression was significantly associated (p < 0.05) with genotype at three single-nucleotide polymorphisms previously identified as being in linkage disequilibrium with schizophrenia.


CONCLUSIONS
Based on the known interactions between CAPON, neuronal nitric oxide synthase (nNOS), and proteins associated with the N-methyl-D-aspartate receptor (NMDAR) complex, overexpression of either CAPON isoform would be expected to disrupt the association between nNOS and the NMDAR, leading to changes consistent with the NMDAR hypofunctioning hypothesis of schizophrenia. This study adds support to a role of CAPON in schizophrenia, produces new evidence implicating this gene in the etiology of bipolar disorder, and suggests a possible mechanism of action of CAPON in psychiatric illness.
Xu
Bin
B
Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America.
Wratten
Naomi
N
Charych
Erik I
EI
Buyske
Steven
S
Firestein
Bonnie L
BL
Brzustowicz
Linda M
LM
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000328:Adult; D001483:Base Sequence; D001714:Bipolar Disorder / Q000503:physiopathology*; D002102:Cadaver; D016022:Case-Control Studies; D005260:Female; D005333:Fetus; D020869:Gene Expression Profiling; D015723:Gene Library; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017397:Prefrontal Cortex / Q000502:physiology*; D020033:Protein Isoforms; D012559:Schizophrenia / Q000503:physiopathology*
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human; D020033:Protein Isoforms