| 1 | Hum. Mutat. 2004 Jul 24: 35-42 |
|---|---|
| PMID | 15221787 |
| Title | Functional analysis of polymorphisms in the promoter regions of genes on 22q11. |
| Abstract | Segmental aneusomy, which includes chromosome 22 deletion syndrome (del(22)(q11.2q11.2)), has been associated with DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face (CAF) syndrome, cat-eye综合征（CES），DER（22）综合征和DEL（22）（Q11.2Q11.2）综合征的重复。DEL（22）（Q11.2Q11.2）的成年人可能患有精神病，包括schizophrenia, schizoaffective disorder, and bipolar disorder, suggesting that lower gene dosage leads to a predisposition to these illnesses. In a bid to identify important regulatory polymorphisms (SNPs) that may emulate changes in gene dosage of the genes within the common deletion, we have analyzed the promoter region of 47 genes (44 of which encode a protein with known function) encoding proteins in and around 22q11 for sequence variants. A total of 33 of the promoters contained polymorphisms. Of those, 25 were cloned into a reporter gene vector, pGL3. The relative ability of each promoter haplotype to promote transcription of the luciferase gene was tested in each of two human cell lines (HEK293t and TE671), using a cotransfected CMV-SPAP plasmid as an internal control. Five genes (PRODH,DGCR14, GSTT2, SERPIND1, and a gene tentatively called DKFZP434P211) showed activity differences between haplotypes of greater than 1.5-fold. Of those, PRODH, which encodes proline dehydrogenase, has previously been highlighted in relation toschizophrenia, and the functional promoter polymorphism reported here may be involved in pathogenic mechanisms. |
| SCZ关键字 | schizophrenia |
| 2 | J Neural Transm (Vienna) 2006 Oct 113: 1551-61 |
| PMID | 16432632 |
| Title | Transmission disequilibrium test provides evidence of association between promoter polymorphisms in 22q11 gene DGCR14 and schizophrenia. |
| Abstract | Recent research has suggested that the DiGeorge syndrome critical region gene 14 (DGCR14) exhibits activity differences of more than 1.5 fold between the haplotypes of the variants in the promoter region.DGCR14is located at 22q11.21, an acknowledged region for susceptibility toschizophrenia. To test the hypothesis thatDGCR14may be involved in the etiology of the disease, we carried out a family-based association study between the reported functional markers andschizophreniain 235 Chinese Han trios. We found significant evidence of preferential transmission of the promoter variants ofDGCR14在所有的三人小组(p -最好value = 0.00038, Global p-value = 0.0008). The positive results have suggested thatDGCR14is likely to play an important role in the etiology ofschizophreniain the Chinese Han population. |
| SCZ关键字 | schizophrenia |
| 3 | Genetics 2014 Nov 198: 1101-15 |
| PMID | 25194163 |
| Title | Systematic analyses of rpm-1 suppressors reveal roles for ESS-2 in mRNA splicing in Caenorhabditis elegans. |
| Abstract | The PHR (Pam/Highwire/RPM-1) family of ubiquitin E3 ligases plays conserved roles in axon patterning and synaptic development. Genetic modifier analysis has greatly aided the discovery of the signal transduction cascades regulated by these proteins. In Caenorhabditis elegans, loss of function in rpm-1 causes axon overgrowth and aberrant presynaptic morphology, yet the mutant animals exhibit little behavioral deficits. Strikingly, rpm-1 mutations strongly synergize with loss of function in the presynaptic active zone assembly factors, syd-1 and syd-2, resulting in severe locomotor deficits. Here, we provide ultrastructural evidence that double mutants, between rpm-1 and syd-1 or syd-2, dramatically impair synapse formation. Taking advantage of the synthetic locomotor defects to select for genetic suppressors, previous studies have identified the DLK-1 MAP kinase cascade negatively regulated by RPM-1. We now report a comprehensive analysis of a large number of suppressor mutations of this screen. Our results highlight the functional specificity of the DLK-1 cascade in synaptogenesis. We also identified two previously uncharacterized genes. One encodes a novel protein, SUPR-1, that acts cell autonomously to antagonize RPM-1. The other affects a conserved protein ESS-2, the homolog of human ES2 orDGCR14. Loss of function in ess-2 suppresses rpm-1 only in the presence of a dlk-1 splice acceptor mutation. We show that ESS-2 acts to promote accurate mRNA splicing when the splice site is compromised. The humanDGCR14/ES2 resides in a deleted chromosomal region implicated in DiGeorge syndrome, and its mutation has shown high probability as a risk factor forschizophrenia. Our findings provide the first functional evidence that this family of proteins regulate mRNA splicing in a context-specific manner. |
| SCZ关键字 | schizophrenia |