Genetic Variations of Human Neuropsin Gene and Psychiatric Disorders: Polymorphism Screening and Possible Association with Bipolar Disorder and Cognitive Functions

Abstract

Human neuropsin (NP) (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders, and cognitive ability. Polymorphism screening was performed for the entire hNP gene. The core promoter region was determined and whether or not transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of five single-nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n ¼ 439), major depression (n ¼ 409), bipolar disorder (n ¼ 207), and controls (n ¼ 727). A possible association of the hNP genotype with memory index (assessed with Wechsler Memory Scale, revised, WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAIS-R) was examined in healthy controls (n ¼ 166). A total of 28 SNPs, including nine novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3 0 regulatory region; odds ratio 1.48, 95% confidential interval 1.16-1.88, P ¼ 0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed between SNP23 and attention/concentration sub-scale score of WMS-R (P ¼ 0.016) and verbal IQ (Po0.001). Genetic variation of the hNP gene may contribute to molecular mechanisms of bipolar disorder and some aspects of memory and intelligence.

Processing of Neuregulin-1 by Neuropsin Regulates GABAergic Neuron to Control Neural Plasticity of the Mouse Hippocampus

“…Human neuropsin is thought to influence cognitive brain function, as single nucleotide polymorphisms (SNPs) are associated with attention/concentration and verbal IQ disorders and with bipolar disorder (Izumi et al, 2008). In animal experiments, neuropsin gene deficiency causes severe impairments in the early phase (E-) of long-term potentiation (LTP), in late-associativity (comprising processes of crosssynaptic interventions within several minutes after induction late phase of LTP), and in spatial working memory (Tamura et al, 2006;Ishikawa et al, 2008).…”

“…Interestingly, neuropsin knock-out mice represent a similar phenotype, with spatial working memory impairment (Tamura et al, 2006) and intact reference memory, as well as increased anxiety behavior . Linkage analysis in humans has identified Nrg-1 as a susceptibility gene for bipolar disorder and schizophrenia (Stefansson et al, 2002;Green et al, 2005) and the neuropsin gene as a susceptibility gene for bipolar disorder (Izumi et al, 2008). Although linkage of the neuropsin gene to schizophrenia was not significant in Japanese populations, a Val286Ile missense mutation in exon 6 of klk8 (SNP22) was detected in a rare case of severe schizophrenia (Izumi et al, 2008).…”

“…Linkage analysis in humans has identified Nrg-1 as a susceptibility gene for bipolar disorder and schizophrenia (Stefansson et al, 2002;Green et al, 2005) and the neuropsin gene as a susceptibility gene for bipolar disorder (Izumi et al, 2008). Although linkage of the neuropsin gene to schizophrenia was not significant in Japanese populations, a Val286Ile missense mutation in exon 6 of klk8 (SNP22) was detected in a rare case of severe schizophrenia (Izumi et al, 2008). Our study provides a new insight into a psychiatry-related signaling system: the neuropsin-NRG-1-ErbB4-GABAergic connection.…”

Human Neuropsin Gene in Depression

“…The regular form is called type 1; type 2 contains a 135-bp insertion of 5' upstream region of exon 3. Type 2 is a hominoid-specific splicing form and is expressed as abundantly as the type 1 in the human brain (Izumi et al 2008).…”

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

“…In line with this proposed function, genetic variations of KLK8 in the 3′ regulatory region of the gene have been observed in patients with manic-depressive disorder and cognitive impairment (Izumi et al, 2008). Human and mouse KLK8 share about 80% identical residues in the active protease domain harboring the conserved sequon at Asn95 (Figure 2).…”