| 1 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Nov 139B: 69-72 |
|---|---|
| PMID | 16152568 |
| Title | Transmission disequilibrium suggests a role for the sulfotransferase-4A1 gene in schizophrenia. |
| Abstract | Previous studies suggest a role for chromosome 22q13 inschizophrenia. This segment of chromosome 22 contains the sulfotransferase-4A1 (SULT4A1) gene, which encodes an enzyme thought to be involved in neurotransmitter metabolism in the central nervous system. To evaluate this candidate, we developed a microsatellite marker targeting a polymorphism in its 5' nontranslated region (D22s1749E). Using samples obtained from the National Institutes of Mental HealthschizophreniaGenetics Initiative, we evaluated 27 families having multiple siblings withschizophreniaandschizophrenia-spectrum disorders for transmission disequilibrium (TDT) of this marker along with three single nucleotide polymorphisms (SNPs) spanning a 37 kb segment containing theSULT4A1gene. TDT for D22s1749E was significant (P < 0.05), with a tendency for the 213 nt allele to be preferentially transferred to affected children (P = 0.0079). Global chi-square values for haplotypes involving the SNPs (ss146366, ss146407, and ss146420) and D22s1749E, also showed significant TDT values (P = 0.0006-0.0016). Consequently, we proposed that Sult4A merited more careful scrutiny as a candidate gene forschizophreniasusceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 2 | Psychiatr. Genet. 2007 Oct 17: 292-8 |
| PMID | 17728668 |
| Title | Evidence for two schizophrenia susceptibility genes on chromosome 22q13. |
| Abstract | Previous linkage scans and meta-analyses forschizophreniasusceptibility loci failed to include the most distal portion of chromosome 22q. Accordingly, 27 families having individuals affected withschizophreniaandschizophrenia-spectrum disorders were analyzed using a set of highly informative markers covering all of chromosome 22q. Microsatellite and single nucleotide polymorphism markers were evaluated by nonparametric linkage, parametric linkage, and transmission disequilibrium testing of 22q. The maximum nonparametric logarithm of odd scores were 2.9 (P=0.0016) forschizophreniaand 2.7 (P=0.003) for a broader disease definition that includedschizotypalpersonality disorder-both at 44.5 cM within theSULT4A1locus. Parametric models assuming dominant modes of inheritance and genetic heterogeneity gave maximum multipoint logarithm of odd scores for the broader disease definition at theSULT4A1locus of 3.3 (P=0.0006) and single point logarithm of odd scores of 3.1-4.8 forSULT4A1markers (P=0.000015-0.0005). A distal locus, centered at 61 cM, shows a maximum nonparametric logarithm of odd scores of 1.5 (P=0.072) for the broader disease definition. Transmission disequilibrium testing for three adjacent microsatellite markers located near the distal linkage peak revealed significant values for marker D22s526 forschizophrenia-0.14 (P = 0.0016)和更广泛的疾病定义s includingschizotypalpersonality disorder (P=0.0002-0.0003), and bothschizotypalpersonality disorder plus schizoaffective disorder (P=0.00001-0.000077). At least two separable, but closely linked, loci within 22q13 influencing susceptibility toschizophrenia频谱紊乱,可能是可能的。 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 3 | Psychiatr. Genet. 2007 Oct 17: 292-8 |
| PMID | 17728668 |
| Title | Evidence for two schizophrenia susceptibility genes on chromosome 22q13. |
| Abstract | Previous linkage scans and meta-analyses forschizophreniasusceptibility loci failed to include the most distal portion of chromosome 22q. Accordingly, 27 families having individuals affected withschizophreniaandschizophrenia-spectrum disorders were analyzed using a set of highly informative markers covering all of chromosome 22q. Microsatellite and single nucleotide polymorphism markers were evaluated by nonparametric linkage, parametric linkage, and transmission disequilibrium testing of 22q. The maximum nonparametric logarithm of odd scores were 2.9 (P=0.0016) forschizophreniaand 2.7 (P=0.003) for a broader disease definition that includedschizotypalpersonality disorder-both at 44.5 cM within theSULT4A1locus. Parametric models assuming dominant modes of inheritance and genetic heterogeneity gave maximum multipoint logarithm of odd scores for the broader disease definition at theSULT4A1locus of 3.3 (P=0.0006) and single point logarithm of odd scores of 3.1-4.8 forSULT4A1markers (P=0.000015-0.0005). A distal locus, centered at 61 cM, shows a maximum nonparametric logarithm of odd scores of 1.5 (P=0.072) for the broader disease definition. Transmission disequilibrium testing for three adjacent microsatellite markers located near the distal linkage peak revealed significant values for marker D22s526 forschizophrenia-0.14 (P = 0.0016)和更广泛的疾病定义s includingschizotypalpersonality disorder (P=0.0002-0.0003), and bothschizotypalpersonality disorder plus schizoaffective disorder (P=0.00001-0.000077). At least two separable, but closely linked, loci within 22q13 influencing susceptibility toschizophrenia频谱紊乱,可能是可能的。 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 4 | Schizophr. Res. 2008 Dec 106: 258-64 |
| PMID | 18823757 |
| Title | Association of Sult4A1 SNPs with psychopathology and cognition in patients with schizophrenia or schizoaffective disorder. |
| Abstract | A number of genes located on chromosome 22q11-13, including catechol-O-methyltransferase (COMT), are potentialschizophreniasusceptibility genes. Recently, the sulfotransferase-4A1 (SULT4A1) locus within chromosome 22q13 was reported to be linked toschizophreniain a family TDT study.SULT4A1is related to metabolism of monoamines, particularly dopamine and norepinephrine, both of which have been implicated in the pathophysiology of the psychopathology and cognitive dysfunction components ofschizophrenia. An available, prospectively collected data base was interrogated to determine how threeSULT4A1SNPs: rs138060, rs138097, and rs138110, previously shown to be associated withschizophreniamight be associated with psychopathology, cognition, and quality of life in a sample of 86 Caucasian patients withschizophreniaor schizoaffective disorder. The majority of patients met criteria for treatment resistantschizophreniaand had been drug-free for one week or longer at the time of evaluation. The major findings were: 1) patients heterozygous (T/G) for rs138060 had significantly worse Brief Psychiatric Rating Scale (BPRS) Total and anxiety/depression sub-scale scores, and higher Scale for the Assessment of Positive Symptoms (SAPS) Total scores than G/G homozygous patients; and 2) patients heterozygous (A/G) for rs138097 demonstrated significantly worse performance on neuropsychological testing, specifically on tests of executive function and working memory, compared to patients homozygous for the G and A alleles. RS138110 was unrelated to psychopathology and cognition. These results provide the first evidence of how genetic variation inSULT4A1may be related to clinical symptoms and cognitive function inschizophrenia, and permit future studies to attempt to replicate these potentially important findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 5 | Int. J. Biochem. Cell Biol. 2008 -1 40: 2686-91 |
| PMID | 18248844 |
| Title | Sulfotransferase 4A1. |
| Abstract | 在本文中,我们强调物理和enzymatic properties of the novel human sulfotransferase,SULT4A1. The gene is most highly expressed in selective regions of the brain, although work to date has failed to identify any specific endogenous substrate for the enzyme.SULT4A1shares low homology with other human sulfotransferases. Nevertheless, it is highly conserved between species. Despite the low homology, it is structurally very similar to other cytosolic sulfotransferases with a conserved substrate binding domain, dimerization site and partial cofactor binding sites. However, the catalytic cavity is much smaller, and it has been suggested that the cofactor may not be accommodated within it. A recent link between variability in the 5'UTR of theSULT4A1gene andschizophreniahas heightened interest in the endogenous function of the enzyme and its possible role in human disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 6 | Psychiatr. Genet. 2009 Feb 19: 53-5 |
| PMID | 19125109 |
| Title | Lack of exonic sulfotransferase 4A1 mutations in controls and schizophrenia cases. |
| Abstract | Sulfotransferase 4A1 (SULT4A1) is a novel sulfotransferase expressed almost exclusively in the brain. The gene is located on chromosome 22q13.3, a region implicated in predisposition toschizophrenia. Recently, a variable microsatellite region located upstream ofSULT4A1was found to be associated with an increase inschizophreniarisk. We hypothesised that if functional dysregulation ofSULT4A1was involved in the aetiology ofschizophrenia, then genetic variants in the coding sequence ofSULT4A1might be identified in cases compared with controls. To test this, we carried out a mutation analysis of the coding region (exons 2-7) in 71 Australianschizophreniacases and 69 controls. We found no mutations, either synonymous or nonsynonymous, in either cohort. However, intronic variants (IVS5+12 C>T and IVS5+28 G>C) were identified, the frequency of which was not statistically different between cases and controls. The lack of polymorphisms in the coding region of theSULT4A1gene is highly unusual and, along with its high conservation between species, suggests thatSULT4A1may have an important function in vivo. However, our findings do not support the hypothesis that germline mutations in the coding region ofSULT4A1contribute to susceptibility toschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 7 | Mol. Pharmacol. 2010 Sep 78: 503-10 |
| PMID | 20571078 |
| Title | Regulation of mouse brain-selective sulfotransferase sult4a1 by cAMP response element-binding protein and activating transcription factor-2. |
| Abstract | Sulfotransferase 4A1 (SULT4A1) is a novel cytosolic sulfotransferase that is primarily expressed in the brain. To date, no significant enzyme activity or biological function for the protein has been identified, although it is highly conserved between species. Mutations in theSULT4A1gene have been linked toschizophreniasusceptibility, and recently, its stability was shown to be regulated by Pin1, a peptidyl-prolyl cis-trans isomerase implicated in several neurodegenerative diseases. In this study, we investigated the transcriptional regulation of mouseSULT4A1. Using a series of promoter deletion constructs, we identified three cAMP-responsive elements (CREs) that were required for maximal promoter activity. The CREs are located within 100 base pairs of the major transcription start site and are also present in the same region of the humanSULT4A1promoter. Electrophoretic mobility shift assays (EMSAs) identified two specific complexes that formed on each of the CREs. One complex contained cAMP response element-binding protein (CREB), and the other contained activating transcription factor-2 (ATF-2) and c-Jun. Overexpression of CREB or ATF-2 increased not only reporter promoter activity but also endogenousSULT4A1mRNA levels in Neuro2a cells. Moreover, [d-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) treatment increased both reporter promoter activity andSULT4A1levels in mu-opioid receptor expressing Neuro2a/mu-opioid receptor cells, and EMSAs showed this to be due to increased binding of CREB and ATF-2 to theSULT4A1promoter. We also show that DAMGO treatment increasesSULT4A1mRNA and protein levels in primary mouse neurons. These results suggest thatSULT4A1is a target gene for the mu-opioid receptor signaling pathway and other pathways involving activation of CREB and ATF-2. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 8 | Prim Care Companion CNS Disord 2012 -1 14: -1 |
| PMID | 23106027 |
| Title | Sulfotransferase 4A1 Haplotype 1 (SULT4A1-1) Is Associated With Decreased Hospitalization Events in Antipsychotic-Treated Patients With Schizophrenia. |
| Abstract | To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predictor of hospitalization events due to the exacerbation ofschizophreniafor patients treated with antipsychotic medications. Haplotypes were determined using single nucleotide polymorphism data. The study included 417 white subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study with a DSM-IV diagnosis ofschizophrenia. Patients were assigned to 1 of 4 atypical antipsychotics (olanzapine, quetiapine, risperidone, or ziprasidone) or to the first-generation antipsychotic perphenazine. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to measure if haplotype status impacted hospitalization events for these 5 treatments. Haplotype status was evaluated for its relationship to hospitalization events regardless of treatment and for the individual treatments, with or without previous exacerbation. Data for the CATIE study were collected from January 2001 to December 2004. The current post hoc analysis was performed between May 2011 and August 2011. In phase 1 of the trial, considering only the first hospitalization events, the haplotype had a significant impact on hospitalization events, with a hazard ratio forSULT4A1-1(-) versusSULT4A1-1(+) of 2.54 (P = .048). When prior exacerbation was included in the model for phase 1, the hazard ratio was 2.34 (P = .072) considering only the first hospitalization event and 2.71 (P = .039) considering all hospitalization events in the phase. When data for all phases were evaluated,SULT4A1-1(-) status was associated with increased hospitalization risk for subjects treated with olanzapine, with a hazard ratio of 8.26 (P = .041), and possibly for subjects treated with quetiapine, with a hazard ratio of 6.80 (P = .070). TheSULT4A1-1 haplotype may be an important predictor of risk of hospitalization.SULT4A1-1(+) status was significantly associated with decreased risk of hospitalization when the subjects were treated with olanzapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 9 | Pharmacogenomics 2014 -1 15: 1557-64 |
| PMID | 25340730 |
| Title | SULT4A1 haplotype: conflicting results on its role as a biomarker of antipsychotic response. |
| Abstract | Based on previous pharmacogenetic findings, we investigated the possible association betweenSULT4A1-1 haplotype and antipsychotic treatment response. Using Mixed Model Repeated Measures, we tested the relationship betweenSULT4A1-1 status (+carrier, -noncarrier) and clinical improvement (in Positive and Negative Syndrome Scale total score) among European ancestry patients treated with paliperidone extended release (n=937), paliperidone palmitate (n=990), risperidone (n=507) and olanzapine (n=381) in 12schizophrenia, two schizoaffective disorder and three bipolar I disorder trials.SULT4A1-1 haplotype was determined using tagging SNP rs763120. There was no significant difference betweenSULT4A1-1(+) andSULT4A1-1(-) patients for treatment response to paliperidone or olanzapine.SULT4A1-1(-) patients had better treatment response to risperidone in oneschizophreniatrial, but not in anotherschizophreniatrial or bipolar mania trial. 跨三个精神障碍(n = 2815病人s), we observed no consistent association betweenSULT4A1-1 status and atypical antipsychotic effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 10 | PLoS ONE 2014 -1 9: e101520 |
| PMID | 24988429 |
| Title | 表达式of the orphan cytosolic sulfotransferase SULT4A1 and its major splice variant in human tissues and cells: dimerization, degradation and polyubiquitination. |
| Abstract | The cytosolic sulfotransferaseSULT4A1is highly conserved between mammalian species but its function remains unknown. Polymorphisms in theSULT4A1gene have been linked to susceptibility toschizophrenia. There are 2 majorSULT4A1transcripts in humans, one that encodes full length protein (wild-type) and one that encodes a truncated protein (variant). Here, we investigated the expression ofSULT4A1in human tissues by RT-PCR and found the wild-type mRNA to be expressed mainly in the brain, gastrointestinal tract and prostate while the splice variant was more widely expressed. In human cell-lines, the wild-type transcript was found in neuronal cells, but the variant transcript was expressed in nearly all other lines examined. Western blot analysis only identifiedSULT4A1protein in cells that expressed the wild-type mRNA. No variant protein was detected in cells that expressed the variant mRNA. Ectopically expressed full lengthSULT4A1protein was stable while the truncated protein was not, having a half-life of approximately 3 hr.SULT4A1was also shown to homodimerize, consistent with other SULTs that contain the consensus dimerization motif. Mutation of the dimerization motif resulted in a monomeric form ofSULT4A1that was rapidly degraded by polyubiquitination on the lysine located within the dimerization motif. These results show thatSULT4A1is widely expressed in human tissues, but mostly as a splice variant that produces a rapidly degraded protein. Dimerization protects the protein from degradation. Since many other cytosolic sulfotransferases possess the conserved lysine within the dimerization motif, homodimerization may serve, in part, to stabilize these enzymes in vivo. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 11 | Drug Metab. Dispos. 2014 May 42: 947-53 |
| PMID | 24553382 |
| Title | Inhibition of SULT4A1 expression induces up-regulation of phototransduction gene expression in 72-hour postfertilization zebrafish larvae. |
| Abstract | Sulfotransferase (SULT) 4A1 is an orphan enzyme that shares distinct structure and sequence similarities with other cytosolic SULTs.SULT4A1is primarily expressed in neuronal tissue and is also the most conserved SULT, having been identified in every vertebrate investigated to date. Certain haplotypes of theSULT4A1gene are correlated with higher baseline psychopathology inschizophrenicpatients, but no substrate or function forSULT4A1has yet been identified despite its high level of sequence conservation. In this study, deep RNA sequencing was used to search for alterations in gene expression in 72-hour postfertilization zebrafish larvae following transientSULT4A1knockdown (KD) utilizing splice blocking morpholino oligonucleotides. This study demonstrates that transient inhibition ofSULT4A1expression in developing zebrafish larvae results in the up-regulation of several genes involved in phototransduction.SULT4A1KD was verified by immunoblot analysis and quantitative real-time polymerase chain reaction (qPCR). Gene regulation changes identified by deep RNA sequencing were validated by qPCR. This study is the first identification of a cellular process whose regulation appears to be associated withSULT4A1expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |