Support for association of the A277C single nucleotide polymorphism in human vesicular monoamine transporter 1 gene with schizophrenia.
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Adult↗
Biomedical subjects
Chia-Hsiang Chen
Publications and source records attributed to Chia-Hsiang Chen.
Psychosis in a patient with Fabry's disease and treatment with aripiprazole.
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Adult↗
Identification of rare mutations of synaptogyrin 1 gene in patients with schizophrenia.
Synaptogyrin 1 gene (SYNGR1) is considered as a positional candidate gene for schizophrenia because of its location at chromosome 22q13, a region linked to schizophrenia, and its reduced expression in postmortem brain of patients with schizophrenia. Additionally, genetic studies also reported association of SYNGR1 is with schizophrenia and bipolar disorder in southern India. Prompted by these findings, we were interested to know if SYNGR1 is also associated with schizophrenia in our population. Therefore, we systematically searched for SYNGR1 mutations in a cohort of Han Chinese patients from Taiwan. Four single nucleotide polymorphisms (SNPs) were identified, including three at the putative core promoter region (g.-673A>C, g.-377G>A and g.-318G>T) that are in strong linkage disequilibrium and one in intron 2 (IVS2-64C>G). Computer program predicts that g.-637A>C and g.318G>T may change transcription binding sites of AP-1 and TGT3, respectively. We further carried out SNP- and haplotype-based case-control association studies of these tress SNPs with schizophrenia. However, no association was detected between these SNPs and schizophrenia in our sample. Nevertheless, we identified several rare mutations in exon 6 of SYNGR1 gene in our patient cohort (n=497), including a 3-bp (AAC) in-frame insertion between codon 202 and 203 (P202_T203insN) in two patients, an A-to-G missense mutation (c.665A>G) at codon 222 (D222G) in one patient, a synonymous mutation (c.669C>T) at codon 223 (T223T) in one patient, and a C-to-T at 3' UTR of SYNGR1 (c.772C>T) in one patient. These are mutations were not found in 507 control subjects, suggesting further functional assays are warranted to verify their relevance to the pathogenesis of schizophrenia.
Adult↗
Orally disintegrating olanzapine for the treatment of a manic patient with esophageal stricture plus chronic pharyngitis.
An orally disintegrating tablet formulation of olanzapine (ODT olanzapine) is designed to dissolve rapidly upon contact with saliva. We describe a manic patient who has an esophageal stricture and chronic pharyngitis, two conditions that impede the swallowing of medications. She was successfully treated for her mania with this orally disintegrating formulation. This case report shows that ODT olanzapine may be useful in the psychiatric management of manic and other patients for whom olanzapine is appropriate, and who have an underlying medical condition that impedes swallowing oral medications.
Administration, Oral↗
A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia.
Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.
Alleles↗
Mutation analysis of DARPP-32 as a candidate gene for schizophrenia.
Dopamine- and cAMP-regulated phosphoprotein of relative molecular mass 32kDa (DARPP-32) plays a pivotal role in the signal transduction of several neurotransmitters and neuromodulators that are implicated in the pathophysiology of a variety of neuropsychiatric disorders. A postmortem study reported a significantly reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, suggesting possible involvement of DARPP-32 in the pathophysiology of schizophrenia. Hence, DARPP-32 was considered as a candidate gene for schizophrenia in this study. We first systemically searched for mutations in the DARPP-32 gene in 50 Han Chinese patients with schizophrenia from Taiwan. Five molecular variants were identified, including a C-to-G substitution (g.-2036C>G) in the putative core promoter that obliterated a predictive AP-2 transcription factor binding site, a G deletion in the untranslated exon 2 (g.1238delG), a G-to-A and an A-to-G substitutions in intron 2 (IVS2+31G>A) and intron 6 (IVS6+32A>G), respectively, and a three-base pair deletion of AGA in exon 6 that resulted in deletion of a glutamate at codon 135 (E135del). Further SNP- and haplotype-based association study in 249 patients and 273 control subjects, however, did not detect association of these markers with schizophrenia. Hence, our results suggest that the reduced DARPP-32 protein in patients with schizophrenia is unlikely caused by mutations in the DARPP-32 gene itself and the DARPP-32 gene is also unlikely a major susceptibility gene for schizophrenia. Nevertheless, the identification of these molecular variants should help the study of gene regulation and structure-function relationship of DARPP-32, and the association study of DARPP-32 gene with other neuropsychiatric disorders.
Alleles↗
Absence of association of a polymorphic GGC repeat at the 5' untranslated region of the reelin gene with schizophrenia.
Reelin is an extracellular matrix glycoprotein that plays an important role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports suggest that reduced reelin expression is associated with human mental illnesses such as schizophrenia, mood disorders and autism. Human reelin cDNA has been cloned and contains a polymorphic GGC repeat at the 5' untranslated region. In view of the possible regulation of reelin gene expression by this GGC polymorphism, we investigated the association of the polymorphic GGC repeat with schizophrenia in a Chinese Han population from Taiwan. We found no differences of allelic and genotypic distributions of the polymorphic GGC triplets between 162 schizophrenic patients and 176 controls in this study. Our findings do not support the involvement of the polymorphic GGC triplets of the reelin gene in the pathogenesis of schizophrenia in the population studied.
5' Untranslated Regions↗
Chronic antipsychotics treatment regulates MAOA, MAOB and COMT gene expression in rat frontal cortex.
Chronic antipsychotic drugs treatment may regulate the expression of a variety of genes in the brain, which may underscore their clinical efficacy and/or side effects. In this study, we measured the mRNA levels of three genes encoding the catabolic enzymes of biogenic amine neurotransmitters, i.e., monoamine oxidase A (MAOA), B (MAOB) and catechol O-methyltransferase (COMT), in rat frontal cortex following 4 weeks' treatment of various antipsychotic drugs using quantitative PCR. Significantly elevated mRNA levels of MAOB and COMT were first observed in frontal cortex of rats treated with risperidone (1mg/kg) when compared to control animals. Further study showed that chronic treatment of olanzapine (2mg/kg), but not haloperidol (1mg/kg) or clozapine (20mg/kg), resulted in significantly increased mRNA levels of MAOA, MAOB and COMT in rat frontal cortex as compared to control animals. These results indicate that chronic treatment of different antipsychotic drugs may differentially regulate the gene expression of three catabolic enzymes of biogenic amine neurotransmitters, and which may partly account for the molecular mechanism of their different clinical efficacy.
Animals↗
Comparative proteome analysis revealed up-regulation of transthyretin in rat brain under chronic clozapine treatment.
Long-term administration of antipsychotic drugs can induce differential expression of various proteins in brain cells, which may underscore the molecular mechanism of their clinical efficacy and/or side effects. We used two-dimensional gel electrophoresis in combination with mass spectrometry to screen differentially expressed proteins in the brain cells of rats under chronic clozapine treatment. We identified a protein, transthyretin, which was significantly up-regulated in the hippocampus of rats after four weeks' treatment of clozapine (20mg/kg) as compared with control animals. Western blot analysis further supported this finding. Besides, we also observed increased transcription of transthyretin mRNA in the cerebral cortex of rats under chronic treatment of clozapine (20mg/kg) or olanzapine (2mg/kg), but not haloperidol (1mg/kg), using real-time quantitative PCR. Transthyretin is a retinol carrier protein, our findings suggest that antipsychotic drugs treatment may affect the retinoid signaling cascade in the brain. Besides, transthyretin is also an indicator of nutritional status; increased transthyretin may be associated with the body weight gain of taking atypical antipsychotic drugs. This study also demonstrates that comparative proteome analysis is a feasible method to study the molecular mechanism of chronic antipsychotic drugs treatment.
Animals↗
Mutation analysis of ARVCF gene on chromosome 22q11 as a candidate for a schizophrenia gene.
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Armadillo Domain Proteins↗
TPMD: a database and resources of microsatellite marker genotyped in Taiwanese populations.
Taiwan Polymorphic Marker Database (TPMD) (http://tpmd.nhri.org.tw/) is a marker database designed to provide experimental details and useful marker information allelotyped in Taiwanese populations accompanied by resources and technical supports. The current version deposited more than 372,000 allelotyping data from 1425 frequently used and fluorescent-labeled microsatellite markers with variation types of dinucleotide, trinucleotide and tetranucleotide. TPMD contains text and map displays with searchable and retrievable options for marker names, chromosomal location in various human genome maps and marker heterozygosity in populations of Taiwanese, Japanese and Caucasian. The integration of marker information in map display is useful for the selection of high heterozygosity and commonly used microsatellite markers to refine mapping of diseases locus followed by identification of disease gene by positional candidate cloning. In addition, our results indicated that the number of markers with heterozygosity over 0.7 in Asian populations is lower than that in Caucasian. To increase accuracy and facilitate genetic studies using microsatellite markers, we also list markers with genotyping difficulty due to ambiguity of allele calling and recommend an optimal set of microsatellite markers for genotyping in Taiwanese, and possible extension of genotyping in other Mongoloid populations.
Alleles↗
Microarray analysis of differentially expressed genes in rat frontal cortex under chronic risperidone treatment.
Long-term administration of antipsychotic drugs can induce differential expression of a variety of genes in the brain, which may underscore the molecular mechanism of the clinical efficacy and/or side effects of antipsychotic drugs. We used cDNA microarray analysis to screen differentially expressed genes in rat frontal cortex under 4 weeks' treatment of risperidone (1 mg/kg). Using real-time quantitative PCR, we were able to verify eight genes, whose expression were significantly upregulated in rat frontal cortex under chronic risperidone treatment when compared with control animals. These genes include receptor for activated protein kinase C, amida, cathepsin D, calpain 2, calcium-independent receptor for alpha-latrotoxin, monoamine oxidase B, polyubiquitin, and kinesin light chain. In view of the physiological function of these genes, the results of our study suggest that chronic risperidone treatment may affect the neurotransmission, synaptic plasticity, and proteolysis of brain cells. This study also demonstrates that cDNA microarray analysis is useful for uncovering genes that are regulated by chronic antipsychotic drugs treatment, which may help bring new insight into the molecular mechanism of antipsychotic drugs.
Animals↗
Intrafamilial phenotype variation in Marfan syndrome ascertained by intragenic linkage analysis.
Marfan syndrome is an autosomal dominant fibrillinopathy caused by mutations of the fibrillin-1 (FBN1) gene. Although linkage analysis is often required to ascertain the disease status in family members, recombination is a problem. We analyzed 6 families including 18 patients using 4 intragenic microsatellite markers, located in intron 1, 5, 28, and 43, respectively, of the FBN1 gene. Haplotypes in all family members could be established, and segregation analysis showed no recombination between the markers and the disease. After confirming the diagnosis, intrafamilial analysis revealed clinical manifestations involving the ocular, cardiac, and skeletal systems. Intragenic linkage analysis in Marfan syndrome is very helpful in its diagnosis and management within affected families.
Adolescent↗
Identification of molecular variants at the promoter region of the human alpha 7 neuronal nicotinic acetylcholine receptor subunit gene but lack of association with schizophrenia.
The human alpha7 neuronal nicotinic receptor subunit gene has been considered as a candidate gene for P50 sensory gating deficit in schizophrenic patients. Because P50 sensory gating deficit is a common neurophysiological dysfunction in patients with schizophrenia and schizophrenia spectrum disorders, it is conceivable to hypothesize that the human alpha7 neuronal nicotinic receptor subunit gene might be a susceptible gene for schizophrenia. Researchers have reported that mutations in the protein-coding sequences of the human alpha7 neuronal nicotinic receptor subunit gene are very rare. Therefore, we searched for mutations at the promoter region of the human alpha7 neuronal nicotinic receptor subunit gene and performed a genetic association study in 249 unrelated Han Chinese schizophrenic patients and 273 non-psychotic subjects from Taiwan. Two molecular variants were identified and designated g.-213G>A and g.-324A>G, respectively. The g.-213G>A variant was found to obliterate a putative NF-1 transcription factor binding site using computer analysis. One out of 249 patients was detected to be a heterozygote for this variant, but none of 273 control subjects was. The g.-324A>G variant was also very rare in both patients and control subjects, only one heterozygote of this variant was identified in 249 patients and 273 control subjects, respectively. Hence, in this study, we did not find mutations in the human alpha7 neuronal nicotinic receptor subunit gene that are associated with schizophrenia in our population.
Adult↗
Mutation analysis of the human dystrobrevin-binding protein 1 gene in schizophrenic patients.
Recent molecular genetic studies have reported a positive association of schizophrenia with several single nucleotide polymorphisms (SNPs) and haplotypes from the human dystrobrevin-binding protein 1 (DTNBP1) gene locus on chromosome 6p. This finding suggests that the DTNBP1 gene is likely a susceptible gene for schizophrenia. Because all the SNPs showing positive association with schizophrenia locate at the intronic sequences of the DTNBP1 gene, we set out to search for mutations in the protein-coding sequences and at the 5' promoter region of the DTNBP1 gene to investigate if the DTNBP1 gene is a schizophrenia-susceptible gene. We directly sequenced the cDNA of DTNBP1 gene in 50 schizophrenic patients and the 5' promoter region of the DTNBP1 genomic DNA in 94 schizophrenia patients. No mutations were identified in either the protein-coding sequences or the 5' promoter region of the human DTNBP1 gene in this sample. Thus, in contrast to prior studies reporting positive association of the DTNBP1 gene with schizophrenia in both Irish and German population, our data indicate that the human DTNBP1 is unlikely a major susceptible gene for schizophrenia in Chinese Han patients from Taiwan.
Adult↗
Elevated adrenomedullin mRNA in lymphoblastoid cells from schizophrenic patients.
Adrenomedullin (ADM) is a 52 amino acid peptide with multiple physiological functions and wide tissue distributions including brain. Recently, elevated plasma levels of ADM were found in patients with schizophrenia, bipolar affective disorder and autism, suggesting the involvement of ADM in the pathophysiology of mental diseases. Using real-time quantitative PCR, we compared the ADM mRNA levels in lymphoblastoid cell lines between schizophrenic patients and controls. Male but not female schizophrenia patients had 2- to 3-fold higher ADM mRNA levels than controls (p<0.01). Our data support that ADM may be associated with the pathophysiology of schizophrenia, although the cause of the association needs further study.
Adrenomedullin↗
No association of a dodecamer duplication in the human opposite paired (HOPA) gene with mental retardation and schizophrenia in Chinese patients from Taiwan.
The human opposite paired-containing (HOPA) gene is believed to be a co-activator of the thyroid hormone receptor and involved in thyroid hormone signal transduction. The gene consists of 45 exons and includes a dodecamer duplication in exon 43, which has been reported to be associated with mental retardation, autism, psychiatric disorders and hypothyroidism. We were interested to know if the 12-bp duplication variant of the HOPA gene is a risk factor for mental retardation and schizophrenia in the Chinese population. We investigated the prevalence of the 12-bp variant in a sample of Chinese mental retardation and schizophrenic patients from Taiwan by PCR-based genotyping. None of the mentally retarded and schizophrenic patients were found to have this dodecamer duplication variant. Our results indicate that the HOPA polymorphism might be very rare in our population and is unlikely to be a major risk factor for mental retardation and schizophrenia in the Chinese population.
Alleles↗
Mutation analysis of synapsin III gene in schizophrenia.
Synapsin III is a new synapsin family gene with the putative function of synaptogenesis regulation and neurotransmitter release in the brain. The gene was mapped to 22q12-q13, a schizophrenia susceptible region gene as suggested by several linkage studies. Hence, the synapsin III gene is considered a candidate gene of schizophrenia. We systematically sequenced the protein coding and 5'-promoter regions of the synapsin III gene to look for mutations in 62 Han Chinese schizophrenic patients from Taiwan with positive family history. Further case-control association study was performed among 163 patients and 151 controls using the genetic polymorphic markers identified from these 62 patients. Three single nucleotide polymorphisms (SNPs) were identified: g.-631C > G and g.-196G>A at 5'-promoter region, and g.69G>A at exon 1. Besides, no other mutations were identified in these patients. The g.69G>A polymorphism does not alter the amino acid threonine at codon 23 (ACG>ACA). Further case-control association studies also did not find significant differences of genotype or allele frequency distributions of these three polymorphisms between 163 patients and 151 non-psychotic comparison individuals. Hence, our data are not in favor of a large effect of synapsin III gene in the pathogenesis of schizophrenia.
Asian People↗