RGS4 is not a susceptibility gene for schizophrenia in Japanese: association study in a large case-control population.

The regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ErbB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p=0.92; SNP 4 (rs951436), p=0.91; SNP 7 (rs951439), p=0.27; and SNP 18 (rs2661319), p=0.43. A haplotype block constructed by these SNPs spans the 5' flanking region to the 5' mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population.

PICK1 is not a susceptibility gene for schizophrenia in a Japanese population: association study in a large case-control population.

The protein interacting with C-kinase 1 (PICK1) has been implicated in the susceptibility to schizophrenia. PICK1 interacts with enzymes and receptors that play roles in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two studies reported associations between schizophrenia and two PICK1 gene polymorphisms, rs3952 in Chinese and Japanese populations and rs2076369 in a Japanese population. We attempted to confirm these associations in a case-control study of 1765 Japanese patients with schizophrenia and 1851 Japanese control subjects. Neither polymorphism was associated with schizophrenia (rs3952, p=0.755; rs2076369, p=0.997). A haplotype block with these polymorphisms spanning the 5' region of the PICK1 gene showed high linkage disequilibrium in the Japanese population (D'=0.98, r(2)=0.34); however, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and polymorphisms of the PICK1 gene identified thus far are unlikely to contribute to genetic susceptibility to schizophrenia in the Japanese population.

The effect on methamphetamine on the mRNA level for 14.3.3 eta chain in the human cultured cells.

14.3.3 protein, a brain-specific protein, is an activator of tyrosine and tryptophan hydroxylases, key enzymes for biosynthesis of dopamine and serotonin. In this article, we describe cloning of cDNA for human brain 14.3.3 eta chain and expression of 14.3.3 eta chain mRNA in some human cultured cells. The cloned cDNA is 1730 bp long and contains 191 bp of a 5'-noncoding region, the complete 738 bp of coding region, and 801 bp of a 3'-noncoding region, containing three polyadenylation signals. This cDNA encoded a polypeptide of 246 amino acids (M(r) 28,196). Furthermore, using in situ hybridization histochemistry, the expression of mRNA for this protein was examined in the rat central nervous system. In situ hybridization histochemistry indicated that 14.3.3 eta chain mRNA is detected not only in the monoamine-synthetic neurons, but also in other neurons in the discrete nuclei, which synthesize neither cathecholamine nor serotonin. Northern blot analysis demonstrated that the addition of methamphetamine into the cultured medium increased the mRNA level for 14.3.3 eta chain in U-251 cells, but did not increase that of GFAP.

14-3-3 protein eta chain gene (YWHAH) polymorphism and its genetic association with schizophrenia.

Recent genetic analyses have suggested a linkage between schizophrenia and the chromosomal region 22q12-q13. 14-3-3 protein, abundant in the brain, mediates interactions between diverse molecules of biological activities; its gene was recently mapped to chromosome 22q12.1-q13.1. We therefore investigated allele frequencies of a variable number of tandem repeat (VNTR) in the 5'-noncoding region of the 14-3-3 eta chain gene in controls and schizophrenics. The frequencies of the two-repeat allele were significantly higher (P < 0.05) in the schizophrenics, and particularly in those with onset before age 22 (early-onset schizophrenics, P < 0.02), than in the controls. The odds ratio was significantly increased in the early-onset schizophrenics homozygous for the two-repeat allele (OR = 3.3, 95% CI = 1.1-9.7). The 14-3-3 eta chain gene is a potential susceptibility gene for schizophrenia, and particularly for early-onset schizophrenia.

Immunohistochemical changes of the transcription regulatory factors in rat striatum after methamphetamine administration.

We have found evidence for cyclic adenosine monophosphate (cAMP) response element (CRE) in the 5'-upstream region of the human 14.3.3 eta chain gene during studies on isolation and structure of animal brain 14.3.3 cDNA and the human 14.3.3 eta chain gene. cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) may bind to this CRE. Since it was considered that these CREBs may play an important role in molecular mechanisms in the brain of animals treated with methamphetamine, we examined the express of CREB and pCREB in rat brain after acute and chronic methamphetamine administrations using antibodies against CREB and pCREB. We observed findings for change in the expression of these factors. Our findings should be discussed in relation to the data of other authors.

Interindividual variation in bromperidol metabolism and relationship to therapeutic effects.

Plasma concentrations of bromperidol (BRP) and reduced bromperidol (RBRP) were determined in 31 patients with schizophrenia who were administered BRP for their psychiatric symptoms. Activities of carbonyl reductase in red blood cells were assayed using BRP as a substrate. Plasma concentrations of BRP and RBRP ranged from 2.2 to 23.5 ng/mL and from 0.2 to 8.2 ng/mL, respectively. RBRP-to-BRP ratios in plasma ranged from 0.01 to 0.94 (mean +/- SD: 0.31 +/- 0.20), values notably lower than the previously reported values of reduced haloperidol to haloperidol (HAL) in the plasma from patients on HAL. The activity of BRP reductase in red blood cells was determined as 6.8-12.3 pmol/hr/10(6) red blood cells, which was at approximately the same level as that of HAL reductase. Patients with positive responses to BRP treatment were evaluated using the Brief Psychiatric Rating Scale. We found that the number of patients who had a positive response to BRP did not increase after BRP plasma levels had reached the level of 12 ng/mL. This finding suggests that a therapeutic plateau in BRP pharmacotherapy of schizophrenia occurs, and there is no advantage to raising the dose once this plateau is reached.

Establishment of enzyme immunoassay for measuring serum sultopride levels.

Measurement of serum sultopride levels was performed using an enzyme immunoassay. Little or no cross-reactivity with metabolites of sultopride and other drugs was found. The results of reproducibility, recovery, and dilution testing were all good enough for clinical use. A comparison between the measurement values of this method (y) with that of high-performance liquid chromatography (x) showed high correlation (n = 211, r = 0.991, p < 0.0001, y = 0.99x + 107.5). In a comparison between the sultopride dose and serum levels in 161 patients, interindividual differences were large (19 times for same doses), implying that the serum level cannot be predicted from the dosage. The method was found to be reliable for serum level measurements of sultopride and useful for monitoring compliance and assessing the optimal dose.

Structural organization and chromosomal assignment of the human 14-3-3 eta chain gene (YWHAH).

14-3-3 protein, a brain-specific protein, is thought to be a multifunctional protein involved in the activation of tyrosine and tryptophan hydroxylases, the inhibition or activation of protein kinase C, and the activation of signal transduction. The human 14-3-3 eta chain gene was isolated and its structure was determined. It is composed of two exons separated by one long intron (approximately 8 kb) and spans about 10 kb. A transcription initiation site was identified by a combination of S1 nuclease mapping, primer extension analysis, and RACE methods. In the 5'-flanking region, we found four GC box sequences, four anti-GC box sequences, a TATA box-like sequence, CAAT box-like sequences, a C/EBP element, two AP-2 sequences, an AP-3 sequence, an Oct-6-like sequence, six E boxes, and a CRE sequence. FISH with DNA probes of the human 14-3-3 eta chain gene mapped the 14-3-3 eta chain gene to chromosome 22q12.1-q13.1.

Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.

We report of a woman aged 52 years born to consanguineous parents and seeking treatment for progressive dementia and delusion. Neurologic examination revealed dementia and emotional instability, indifference, and confabulation. There was also mild spasticity of the bilateral lower limbs. MRI revealed diffuse white matter hyperintensity on T2-weighted images accompanied by hypointense areas on fluid-attenuated inversion recovery images. A homozygous missense mutation was identified in EIF2B5.