Increased Expression in Dorsolateral Prefrontal Cortex of CAPON in Schizophrenia and Bipolar Disorder

Abstract

BackgroundWe 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.Methods and FindingsWe 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.ConclusionBased 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.

CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

“…The higher bands (Ϸ70 kDa) could reflect either posttranslational modification of CAPON or nonspecific crossreactivity. Notably, the ventricular myocardium also displayed a band Ϸ30 kDa in size detected by antibody against the C terminus of CAPON, but not by antibody against an N-terminal epitope, which is consistent with the short-form of CAPON (13). Immunofluorescent staining of freshly isolated ventricular myocytes revealed a cytoplasmic distribution pattern of the soluble CAPON protein with focal accentuation over the perinuclear region and the sarcolemmal membrane (Fig.…”

“…The full-length transcript encompassing 10 exons contains both PTB-and PDZ-binding domains, whereas the C-terminal transcript containing the last 2 exons encodes only the PDZ-binding domain (13). We found that both full-length and short CAPON isoforms are expressed in guinea pig ventricular myocytes using the same CAPON antibody (13) predicted to react with the C terminus of CAPON. The full-length isoform comigrated at the same level as a brain-enriched protein band and a band from HEK293 cells expressing CAPON.…”

“…Since the first identification of CAPON protein in the rat brain (4), Xu et al (13) further found that CAPON protein has two isoforms that are translated from a full-length and a C-terminal splicing variant (13). The full-length transcript encompassing 10 exons contains both PTB-and PDZ-binding domains, whereas the C-terminal transcript containing the last 2 exons encodes only the PDZ-binding domain (13). We found that both full-length and short CAPON isoforms are expressed in guinea pig ventricular myocytes using the same CAPON antibody (13) predicted to react with the C terminus of CAPON.…”

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

“…Blocking the PDZ-domain of NOS-I with small molecule inhibitors has been suggested as a possible therapeutic approach in the treatment of depression, a hypothesis that is supported by preclinical evidence (Doucet et al, 2013). Since we show that expression levels of NOS-I are reduced in rs41279104 risk allele carriers, and since elevated expression of NOS1AP interfering with post-synaptic targeting of NOS-I (Jaffrey et al, 2002;Jaffrey et al, 1998) is elevated in schizophrenic patients (Xu et al, 2005), a comparable approach (i.e., blocking NOS-I -NOS1AP interaction with small molecules) might provide a feasible strategy for treatment at least in patients carrying this risk allele. In this context, it is also interesting to note that another SNP that was associated with schizophrenia in a family-based study (and therefore not included in our meta-analysis) produced elevated NOS1AP promoter activity in human cell lines ).…”

NOS1AP Associates with Scribble and Regulates Dendritic Spine Development

“…The original isoform CAPON (Jaffrey et al, 1998) has also been termed NOS1AP or NOS1AP-L (Carrel et al, 2009). As well, a short isoform containing the last two exons of the NOS1AP gene with a unique 5Ј sequence is known as NOS1AP-S (Xu et al, 2005). Since our isoform is longer than the originally identified NOS1AP/CAPON/NOS1AP-L isoform, and since it is the third isoform to be described, we have called it NOS1APc.…”