| 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 in schizophrenia. 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 Health schizophrenia Genetics Initiative, we evaluated 27 families having multiple siblings with schizophrenia and schizophrenia-spectrum disorders for transmission disequilibrium (TDT) of this marker along with three single nucleotide polymorphisms (SNPs) spanning a 37 kb segment containing the SULT4A1 gene. 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 for schizophrenia susceptibility. |
| 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 for schizophrenia susceptibility loci failed to include the most distal portion of chromosome 22q. Accordingly, 27 families having individuals affected with schizophrenia and schizophrenia-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) for schizophrenia and 2.7 (P=0.003) for a broader disease definition that included schizotypal personality disorder-both at 44.5 cM within the SULT4A1 locus. Parametric models assuming dominant modes of inheritance and genetic heterogeneity gave maximum multipoint logarithm of odd scores for the broader disease definition at the SULT4A1 locus of 3.3 (P=0.0006) and single point logarithm of odd scores of 3.1-4.8 for SULT4A1 markers (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 for schizophrenia (P=0.0016-0.14) and for broader disease definitions including schizotypal personality disorder (P=0.0002-0.0003), and both schizotypal personality disorder plus schizoaffective disorder (P=0.00001-0.000077). At least two separable, but closely linked, loci within 22q13 influencing susceptibility to schizophrenia-spectrum disorders, might be possible. |
| 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 for schizophrenia susceptibility loci failed to include the most distal portion of chromosome 22q. Accordingly, 27 families having individuals affected with schizophrenia and schizophrenia-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) for schizophrenia and 2.7 (P=0.003) for a broader disease definition that included schizotypal personality disorder-both at 44.5 cM within the SULT4A1 locus. Parametric models assuming dominant modes of inheritance and genetic heterogeneity gave maximum multipoint logarithm of odd scores for the broader disease definition at the SULT4A1 locus of 3.3 (P=0.0006) and single point logarithm of odd scores of 3.1-4.8 for SULT4A1 markers (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 for schizophrenia (P=0.0016-0.14) and for broader disease definitions including schizotypal personality disorder (P=0.0002-0.0003), and both schizotypal personality disorder plus schizoaffective disorder (P=0.00001-0.000077). At least two separable, but closely linked, loci within 22q13 influencing susceptibility to schizophrenia-spectrum disorders, might be possible. |
| 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 potential schizophrenia susceptibility genes. Recently, the sulfotransferase-4A1 (SULT4A1) locus within chromosome 22q13 was reported to be linked to schizophrenia in a family TDT study. SULT4A1 is 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 of schizophrenia. An available, prospectively collected data base was interrogated to determine how three SULT4A1 SNPs: rs138060, rs138097, and rs138110, previously shown to be associated with schizophrenia might be associated with psychopathology, cognition, and quality of life in a sample of 86 Caucasian patients with schizophrenia or schizoaffective disorder. The majority of patients met criteria for treatment resistant schizophrenia and 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 in SULT4A1 may be related to clinical symptoms and cognitive function in schizophrenia, 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 | In this review, we highlight the physical and 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. SULT4A1 shares 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 the SULT4A1 gene and schizophrenia has 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 to schizophrenia. Recently, a variable microsatellite region located upstream of SULT4A1 was found to be associated with an increase in schizophrenia risk. We hypothesised that if functional dysregulation of SULT4A1 was involved in the aetiology of schizophrenia, then genetic variants in the coding sequence of SULT4A1 might 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 Australian schizophrenia cases 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 the SULT4A1 gene is highly unusual and, along with its high conservation between species, suggests that SULT4A1 may have an important function in vivo. However, our findings do not support the hypothesis that germline mutations in the coding region of SULT4A1 contribute to susceptibility to schizophrenia. |
| 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 the SULT4A1 gene have been linked to schizophrenia susceptibility, 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 mouse SULT4A1. 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 human SULT4A1 promoter. 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 endogenous SULT4A1 mRNA levels in Neuro2a cells. Moreover, [d-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) treatment increased both reporter promoter activity and SULT4A1 levels 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 the SULT4A1 promoter. We also show that DAMGO treatment increases SULT4A1 mRNA and protein levels in primary mouse neurons. These results suggest that SULT4A1 is 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 of schizophrenia for 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 of schizophrenia. 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 for SULT4A1-1(-) versus SULT4A1-1(+) 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). The SULT4A1-1 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 between SULT4A1-1 haplotype and antipsychotic treatment response. Using Mixed Model Repeated Measures, we tested the relationship between SULT4A1-1 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 12 schizophrenia, two schizoaffective disorder and three bipolar I disorder trials. SULT4A1-1 haplotype was determined using tagging SNP rs763120. There was no significant difference between SULT4A1-1(+) and SULT4A1-1(-) patients for treatment response to paliperidone or olanzapine. SULT4A1-1(-) patients had better treatment response to risperidone in one schizophrenia trial, but not in another schizophrenia trial or bipolar mania trial. Across three psychiatric disorders (n=2815 patients), we observed no consistent association between SULT4A1-1 status and atypical antipsychotic effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |
| 10 | PLoS ONE 2014 -1 9: e101520 |
| PMID | 24988429 |
| Title | Expression of the orphan cytosolic sulfotransferase SULT4A1 and its major splice variant in human tissues and cells: dimerization, degradation and polyubiquitination. |
| Abstract | The cytosolic sulfotransferase SULT4A1 is highly conserved between mammalian species but its function remains unknown. Polymorphisms in the SULT4A1 gene have been linked to susceptibility to schizophrenia. There are 2 major SULT4A1 transcripts in humans, one that encodes full length protein (wild-type) and one that encodes a truncated protein (variant). Here, we investigated the expression of SULT4A1 in 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 identified SULT4A1 protein in cells that expressed the wild-type mRNA. No variant protein was detected in cells that expressed the variant mRNA. Ectopically expressed full length SULT4A1 protein was stable while the truncated protein was not, having a half-life of approximately 3 hr. SULT4A1 was also shown to homodimerize, consistent with other SULTs that contain the consensus dimerization motif. Mutation of the dimerization motif resulted in a monomeric form of SULT4A1 that was rapidly degraded by polyubiquitination on the lysine located within the dimerization motif. These results show that SULT4A1 is 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. SULT4A1 is primarily expressed in neuronal tissue and is also the most conserved SULT, having been identified in every vertebrate investigated to date. Certain haplotypes of the SULT4A1 gene are correlated with higher baseline psychopathology in schizophrenic patients, but no substrate or function for SULT4A1 has 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 transient SULT4A1 knockdown (KD) utilizing splice blocking morpholino oligonucleotides. This study demonstrates that transient inhibition of SULT4A1 expression in developing zebrafish larvae results in the up-regulation of several genes involved in phototransduction. SULT4A1 KD 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 with SULT4A1 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypal |