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Functional characterization of two variants in the 3'-untranslated region (UTR) of transcription factor 4 gene and their association with schizophrenia in sib-pairs from multiplex families

Mohamed ZI, Tee SF, Chow TJ, Loh SY, Yong HS, Bakar AKA, et al.

Asian J Psychiatr, 2019 Feb;40:76-81.
PMID: 30771755 DOI: 10.1016/j.ajp.2019.02.001

Transcription factor 4 (TCF4) gene plays an important role in nervous system development and it always associated with the risk of schizophrenia. Since miRNAs regulate targetgenes by binding to 3'UTRs of target mRNAs, the functional variants located in 3'UTR of TCF4 are highly suggested to affect the gene expressions in schizophrenia. To test the hypothesis regarding the effects of the variants located in 3'UTR of TCF4, we conducted an in silico analysis to identify the functional variants and their predicted functions. In this study, we sequenced the 3'UTR of TCF4 in 13 multiplex schizophrenia families and 14 control families. We found two functional variants carried by three unrelated patients. We determined that the C allele of rs1272363 and the TC insert of rs373174214 might suppress post- transcriptional expression. Secondly, we cloned the region that flanked these two variants into a dual luciferase reporter system and compared the luciferase activities between the pmirGLO-TCF4 (control), pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263. Both pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263 caused lower reporter gene activities, as compared to the control. However, only the C allele of rs1272363 reduced the luciferase activity significantly (p = 0.0231). Our results suggested that rs1273263 is a potential regulator of TCF4 expression, and might be associated with schizophrenia.

Matched MeSH terms: 3' Untranslated Regions/genetics*
Introduction of a single-nucleotide variant, rs16851030, into the ADORA1 gene increased cellular susceptibility to hypoxia

Wong PK, Syafruddin SE, Cheah FC, Azmi N, Ng PY, Chua EW

Per Med, 2024;21(6):353-366.
PMID: 39440484 DOI: 10.1080/17410541.2024.2412514

Aim: Rs16851030, a single-nucleotide variant located in the 3'-untranslated region of the ADORA1 gene, has been proposed as a potential marker of caffeine sensitivity in apnea of prematurity. Besides, it is associated with aspirin-induced asthma and the development of acute chest syndrome. However, its functional significance is still unconfirmed. This study aimed to elucidate the functional impact of rs16851030 by using CRISPR/Cas9 approach to induce the DNA variant and attendant physiological changes.Methods: Rs16851030 was introduced into HEK293 cells via homology-directed repair (HDR). Edited cells were fluorescence-enriched, sorted, isolated, and expanded into single-cell-derived clones. The edit was confirmed by Sanger sequencing. RNA sequencing was used to analyze affected pathways.Results: Rs16851030-mutant cells showed increased susceptibility to hypoxia, a condition related to apnea of prematurity. After 24 h of hypoxia, the viability of mutant clones 1 and 2 was low compared with wild-type cells (75.45% and 74.47% vs. 96.34%). RNA sequencing revealed transcriptomic changes linked to this increased vulnerability.Conclusion: Rs16851030 impairs cellular resistance to hypoxia, suggesting its role in conditions like apnea of prematurity. Further research should investigate the molecular mechanisms and transcriptomic alterations caused by rs16851030 under hypoxic conditions.

Matched MeSH terms: 3' Untranslated Regions/genetics
Cellular proteins bind to the 3' and 5' untranslated regions of dengue 2 virus genome

Ong CC, Lam SK, AbuBakar S

Malays J Pathol, 1998 Jun;20(1):11-7.
PMID: 10879258

In vitro generated cloned full length dengue 2 virus untranslated regions (UTRs) were used in RNA gel mobility shift assays to examine cellular factors binding to the virus genomes. Cellular factors in lysates of Vero (monkey) and C6/36 (mosquito) cells bound specifically and non-specifically to the dengue 2 virus 3' UTR. Non-specific interaction with the 5' UTR, resulting in formation of at least 4 band shift complexes was noted with lysate of the C6/36 cells only. Pre-treating the cell lysates with proteinase K affected binding of cellular factors to the dengue 2 virus UTRs, suggesting that the cellular factors were proteins. These findings suggest that cellular proteins could interact with specific sites on the dengue virus genomes.

Matched MeSH terms: 3' Untranslated Regions/genetics
Association of functional polymorphisms in 3'-untranslated regions of COMT, DISC1, and DTNBP1 with schizophrenia: a meta-analysis

Mohamed ZI, Tee SF, Tang PY

Psychiatr Genet, 2018 12;28(6):110-119.
PMID: 30252773 DOI: 10.1097/YPG.0000000000000210

INTRODUCTION: In recent years, various studies have accumulated evidence of the involvement of single nucleotide polymorphisms (SNPs) in introns and exons in schizophrenia. The association of functional SNPs in the 3'-untranslated regions with schizophrenia has been explored in a number of studies, but the results are inconclusive because of limited meta-analyses. To systematically analyze the association between SNPs in 3'-untranslated regions and schizophrenia, we conducted a meta-analysis by combining all available studies on schizophrenia candidate genes.
MATERIALS AND METHODS: We searched candidate genes from the schizophrenia database and performed a comprehensive meta-analysis using all the available data up to August 2017. The association between susceptible SNPs and schizophrenia was assessed by the pooled odds ratio with 95% confidence interval using fixed-effect and random-effect models.
RESULTS: A total of 21 studies including 8291 cases and 9638 controls were used for meta-analysis. Three investigated SNPs were rs165599, rs3737597, and rs1047631 of COMT, DISC1, and DTNBP1, respectively. Our results suggested that rs3737597 showed a significant association with schizophrenia in Europeans (odds ratio: 1.584, P: 0.002, 95% confidence interval: 1.176-2.134) under a random-effect framework.
CONCLUSION: This meta-analysis indicated that rs3737597 of DISC1 was significantly associated with schizophrenia in Europeans, and it can be suggested as an ethnic-specific risk genetic factor.

Matched MeSH terms: 3' Untranslated Regions/genetics
Fulltext Descriptive distribution and phylogenetic analysis of feline infectious peritonitis virus isolates of Malaysia

Sharif S, Arshad SS, Hair-Bejo M, Omar AR, Zeenathul NA, Fong LS, et al.

Acta Vet Scand, 2010 Jan 06;52(1):1.
PMID: 20053278 DOI: 10.1186/1751-0147-52-1

The descriptive distribution and phylogeny of feline coronaviruses (FCoVs) were studied in cats suspected of having feline infectious peritonitis (FIP) in Malaysia. Ascitic fluids and/or biopsy samples were subjected to a reverse transcription polymerase chain reaction (RT-PCR) targeted for a conserved region of 3'untranslated region (3'UTR) of the FCoV genome. Eighty nine percent of the sampled animals were positive for the presence of FCoV. Among the FCoV positive cats, 80% of cats were males and 64% were below 2 years of age. The FCoV positive cases included 56% domestic short hair (DSH), 40% Persian, and 4% Siamese cats. The nucleotide sequences of 10 selected amplified products from FIP cases were determined. The sequence comparison revealed that the field isolates had 96% homology with a few point mutations. The extent of homology decreased to 93% when compared with reference strains. The overall branching pattern of phylogenetic tree showed two distinct clusters, where all Malaysian isolates fall into one main genetic cluster. These findings provided the first genetic information of FCoV in Malaysia.

Matched MeSH terms: 3' Untranslated Regions/genetics
Fulltext Lack of association between RANTES-28, SDF-1 gene polymorphisms and systemic lupus erythematosus in the Malaysian population

Lian LH, Kee BP, Ng HL, Chua KH

Genet. Mol. Res., 2011;10(4):2841-50.
PMID: 22095608 DOI: 10.4238/2011.November.17.2

Regulated on activation, normal T-cell expressed and secreted (RANTES) and stromal cell-derived factor 1 (SDF-1) are members of the CC- and CXC-chemokine families, respectively. Both genes have been postulated to be involved in the pathogenesis of systemic lupus erythematosus (SLE). We analyzed position 28 of the RANTES gene promoter region, as well as the SNP observed in the 3' UTR of the SDF-1 gene at position 801, in 130 patients presenting SLE at the Malaya University Medical Centre. Screening of 130 healthy volunteer controls using RFLP was also performed. RANTES-28 polymorphism analysis showed no significant (P = 0.3520) relationship, even though homozygous C/C was more frequent in SLE patients (OR = 1.4183) and heterozygous C/G was more frequent in healthy controls (OR = 0.7051). There were no significant (P = 0.2650) associations between A/A (OR = 0.783), G/G (OR = 1.5914) and G/A (OR = 0.8289) genotypes in the SDF-1 gene polymorphism with SLE. We conclude that there is no significant association of RANTES-28 and SDF-1 gene polymorphisms and occurrence of SLE in Malaysia.

Matched MeSH terms: 3' Untranslated Regions/genetics
Fulltext Emergence of Japanese encephalitis virus genotype V in the Republic of Korea

Takhampunya R, Kim HC, Tippayachai B, Kengluecha A, Klein TA, Lee WJ, et al.

Virol J, 2011;8:449.
PMID: 21943222 DOI: 10.1186/1743-422X-8-449

Japanese encephalitis virus (JEV) genotype V reemerged in Asia (China) in 2009 after a 57-year hiatus from the continent, thereby emphasizing a need to increase regional surveillance efforts. Genotypic characterization was performed on 19 JEV-positive mosquito pools (18 pools of Culex tritaeniorhynchus and 1 pool of Cx. bitaeniorhynchus) from a total of 64 positive pools collected from geographically different locations throughout the Republic of Korea (ROK) during 2008 and 2010.

Matched MeSH terms: 3' Untranslated Regions/genetics
Cyp2a5 Promoter-based Gene Reporter Assay: A Novel Design of Cell-based Bioassay for Toxicity Prediction

Abu-Bakar A, Hu H, Lang MA

Basic Clin Pharmacol Toxicol, 2018 Sep;123 Suppl 5:72-80.
PMID: 29788535 DOI: 10.1111/bcpt.13046

The murine cytochrome P450 2a5 (Cyp2a5) gene is regulated by complex interactions of various stress-activated transcription factors (TFs). Elevated Cyp2a5 transcription under chemical-induced stress conditions is achieved by interplay between the various TFs - including as aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2) - at the 'stress-responding' cluster of response elements on the Cyp2a5 promoter, as well as through mRNA stabilization mediated by interaction of the stress-activated heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) with the 3'-UTR of the CYP2A5 mRNA. We designed a unique toxicity pathway-based reporter assay to include regulatory regions from both the 5' and the 3' untranslated regions of Cyp2a5 in a luciferase reporter plasmid to reflect in vivo responses to chemical insult. Human breast cancer MCF-7 cells were stably transfected with pGL4.38-Cyp2a5_Wt3k (wild-type) or mutant - pGL4.38-Cyp2a5_StREMut and pGL4.38-Cyp2a5_XREMut - reporter gene to monitor chemical-induced cellular response mediated by AhR and Nrf2 signalling. The recombinant cells were treated with representative of AhR agonist, polycyclic aromatic hydrocarbons, brominated flame retardant, fluorosurfactant, aromatic organic compound and metal, to determine the sensitivity of the Cyp2a5 promoter-based gene reporter assays to chemical insults by measuring the LC50 and EC50 of the respective chemicals. The three assays are sensitive to sublethal cellular responses of chemicals, which is an ideal feature for toxicity pathway-based bioassay for toxicity prediction. The wild-type reporter responded well to chemicals that activate crosstalk between the AhR and Nrf2, whilst the mutant reporters effectively gauge cellular response driven by either Nrf2/StRE or AhR/XRE signalling. Thus, the three gene reporter assays could be used tandemly to determine the predominant toxicity pathway of a given compound.

Matched MeSH terms: 3' Untranslated Regions/genetics