Could one splicing-site single nucleotide polymorphism cause the MODY2 disease?
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ABSTRACT:
SUBMITTER: Mota S
PROVIDER: S-EPMC4659184 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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Project description:Moyamoya disease (MMD) is a chronic, progressive, cerebrovascular occlusive disorder that displays various clinical features and results in cerebral infarct or hemorrhagic stroke. Specific genes associated with the disease have not yet been identified, making identification of at-risk patients difficult before clinical manifestation. Familial MMD is not uncommon, with as many as 15% of MMD patients having a family history of the disease, suggesting a genetic etiology. Studies of single nucleotide polymorphisms (SNPs) in MMD have mostly focused on mechanical stress on vessels, endothelium, and the relationship to atherosclerosis. In this review, we discuss SNPs studies targeting the genetic etiology of MMD. Genetic analyses in familial MMD and genome-wide association studies represent promising strategies for elucidating the pathophysiology of this condition. This review also discusses future research directions, not only to offer new insights into the origin of MMD, but also to enhance our understanding of the genetic aspects of MMD. There have been several SNP studies of MMD. Current SNP studies suggest a genetic contribution to MMD, but further reliable and replicable data are needed. A large cohort or family-based design would be important. Modern SNP studies of MMD depend on novel genetic, experimental, and database methods that will hopefully hasten the arrival of a consensus conclusion.
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Project description:The study of gene regulatory network and protein-protein interaction network is believed to be fundamental to the understanding of molecular processes and functions in systems biology. In this study, the authors are interested in single nucleotide polymorphism (SNP) level and construct SNP-SNP interaction network to understand genetic characters and pathogenetic mechanisms of complex diseases. The authors employ existing methods to mine, model and evaluate a SNP sub-network from SNP-SNP interactions. In the study, the authors employ the two SNP datasets: Parkinson disease and coronary artery disease to demonstrate the procedure of construction and analysis of SNP-SNP interaction networks. Experimental results are reported to demonstrate the procedure of construction and analysis of such SNP-SNP interaction networks can recover some existing biological results and related disease genes.
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Project description:Comparisons between the sample groups (normal elderly control (NEC) and Alzheimer disease (AD)) allowed the identification of genes with disease expression patterns associated with the glutathione S-transferase M3 single nucleotide polymorphism rs7483. Keywords: biological repeat Peripheral blood mononuclear cells (BMC) were obtained from normal elderly control (NEC) and Alzheimer disease (AD) subjects. Targets from biological replicates of NEC (n=18) and AD (n=16) were generated and the expression profiles were determined using the NIA Human MGC cDNA microarray.
2010-06-24 | E-GEOD-4227 | biostudies-arrayexpress
Project description:XPC DNA repair gene mutations result in the cancer-prone disorder xeroderma pigmentosum. The XPC gene spans 33 kb and has 16 exons (82-882 bp) and 15 introns (0.08-5.4 kb). A 1.6 kb intron was found within exon 5. Sensitive real- time quantitative reverse transcription-polymerase chain reaction methods were developed to measure full-length XPC mRNA (the predominant form) and isoforms that skipped exons 4, 7 or 12. Exon 7 was skipped in approximately 0.07% of XPC mRNAs, consistent with the high information content of the exon 7 splice acceptor and donor sites (12.3 and 10.4 bits). In contrast, exon 4 was skipped in approximately 0.7% of the XPC mRNAs, consistent with the low information content of the exon 4 splice acceptor (-0.1 bits). A new common C/A single nucleotide polymorphism in the XPC intron 11 splice acceptor site (58% C in 97 normals) decreased its information content from 7.5 to 5.1 bits. Fibroblasts homozygous for A/A had significantly higher levels (approximately 2.6-fold) of the XPC mRNA isoform that skipped exon 12 than those homozygous for C/C. This abnormally spliced XPC mRNA isoform has diminished DNA repair function and may contribute to cancer susceptibility.
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Project description:Teleosts show varied master sex determining (MSD) genes and sex determination (SD) mechanisms, with frequent turnovers of sex chromosomes. Tracing the origins of MSD genes and turnovers of sex chromosomes in a taxonomic group is of particular interest in evolutionary biology. Oyster pompano (Trachinotus anak), a marine fish, belongs to the family Carangidae, in which 17b-hydroxysteroid dehydrogenase 1 (hsd17b1) has repeatedly evolved to an MSD gene. Whole-genome resequencing identified a single nucleotide polymorphism (SNP) at chromosome 24 to be strictly associated with phenotypic sex, with females being the heterozygous sex. This SNP is located in a splicing site at the first exon/intron boundary of hsd17b1. The Z-linked SNP results in malfunction of all spliced isoforms, whereas the W-linked isoforms were predicted to have open reading frames that are conserved among vertebrates, suggesting that hsd17b1 is a female-determining gene. The differential alternative splicing patterns of ZZ and ZW genotypes were consistently observed both in undifferentiated stages and differentiated gonads. We observed elevated recombination around the SD locus and no differentiation between Z and W chromosomes. The extreme diversity of mutational mechanisms that hsd17b1 evolves to an MSD gene highlights frequent in situ turnovers between sex chromosomes in the Carangidae.
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Project description:Primary Objective:
Correlation of the skin and/or eye toxicity grade secondary to Cetuximab or Panitumumab and the SNP profile of the Epidermal Growth Factor Receptor (EGFR) domain III region.
Secondary Objectives:
Correlation of SNP profile with indicators of tumour response parameters, such as radiological response, duration of response, time to progression (TTP), overall survival (OS) time, incidence of non-dermatological adverse events.
| 2135070 | ecrin-mdr-crc
Project description:The single nucleotide polymorphism (SNP) site within the aquaporin (AQP)-4 gene exons and its possible role in the pathogenesis of neuromyelitis optica (NMO) were studied. From March 2010 to June 2012, 72 patients with NMO from Xiangyang No. 1 People's Hospital, Hubei University of Medicine were enrolled in the NMO group. At the same time, 80 patients with multiple sclerosis (MS) were enrolled in our study as the MS group. Blood samples were collected and DNA was extracted for analysis of SNP sites of AQP4 gene. Specific site-directed mutagenesis method was used for site-directed mutagenesis on plasmid enhanced green fluorescence protein carrying AQP4 gene. Mutant plasmids were constructed and used for transfecting cell lines. The differences of anti-AQP4 antibody level in the cell line were analyzed. The possible correlation between AQP4 gene SNP sites and the pathogenesis of NMO were analyzed. In the NMO group, 6 SNP sites in AQP4 gene were located in exons 2 and 5. These included R108T, I110N, E280R, D281R, P295R and E317M. There was no SNP site in exons 1, 3 and 4. In the MS group, no SNP site was found in AQP4 gene. R108T, I110N, R108T/I110N, E280R/D281R, P295R and E317M cell lines were constructed in the NMO group, and anti-AQP4 antibody in the serum was compared between R108T/I110N, E280R/D281R and E317M cell lines and the original HEK293T cell line. The difference was statistically significant (P<0.05). The positive rate of anti-AQP4 antibody titer in serum was compared between R108T, I110N, R108T/I110N, E280R/D281R, P295R and E317M cell lines in the NMO group and the original cell line in the MS group. In conclusion, SNP sites in AQP4 gene in patients with NMO may lead to some conformational changes in AQP4 protein. This affects the antigenicity of AQP4 protein. The different intensity of antigen-antibody reaction may cause the differences of titer observed between the different mutant cell lines.
| S-EPMC5740579 | biostudies-literature
Project description:BackgroundTriptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. Triptolide has been shown to induce apoptosis by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak2 transcription, activating MAPK8/JNK signaling and modulating the heat shock responses.ResultsIn the present study, we used lymphoblast cell lines (LCLs) derived from 55 unrelated Caucasian subjects to identify genetic markers predictive of cellular sensitivity to triptolide using genome wide association study. Our results identified SNPs on chromosome 2 associated with triptolide IC50 (p < 0.0001). This region included biologically interesting genes as CFLAR, PPIl3, Caspase 8/10, NFkB and STAT6. Identification of a splicing-SNP rs10190751, which regulates CFLAR alternatively spliced isoforms predictive of the triptolide cytotoxicity suggests its role in triptolides action. Our results from functional studies in Panc-1 cell lines further demonstrate potential role of CFLAR in triptolide toxicity. Analysis of gene-expression with cytotoxicity identified JAK1 expression to be a significant predictor of triptolide sensitivity.ConclusionsOverall out results identified genetic factors associated with triptolide chemo-sensitivity thereby opening up opportunities to better understand its mechanism of action as well as utilize these biomarkers to predict therapeutic response in patients.
| S-EPMC4485866 | biostudies-literature
Project description:Dear Editor, The recent article by Mohammadzadeh et al.[1] on the latest issue of this Journal showed that the T allele +276G/T SNP of ADIPOQ gene is more associated with the increasing risk of coronary artery disease (CAD) in subjects with type 2 diabetes. Adipocytes were described in myocardial tissue of CAD patients and their role recently discussed[2,3]. Susceptibility to CAD by polymorphism in the Q gene of adiponectin has been reported for 3'-UTR, which harbours some genetic loci associated with metabolic risks and atherosclerosis[4]. Actually, previous studies have shown that the haplotype SNP +276G>T was associated with a decreased risk of CAD, after adjustment for potential confounding factors, therefore some controversial opinion still exists[5]. This evidence should be associated with the role exerted by adipocytes and adiponectin in heart physiology. In particular, in hypertensive disorder complicating pregnancy (HDCP), by investigating the population frequency of alleles, genotypes, and haplotypes of two single nucleotide polymorphisms (SNPs), namely +45T>G (rs2241766) and +276G>T (rs1501299), some authors found that the SNP +276 TT genotype was significantly associated with protection against HDCP, when compared to the pooled G genotypes[6]. Moreover, the same +276G/T SNP haplotype was strongly associated with biliary atresia, an intractable neonatal inflammatory and obliterative cholangiopathy, leading to progressive fibrosis and cirrhosis[7]. CAD is closely related to adiponectin biology. The same isoforms of adiponectin seem to be not associated to CAD severity but to glucose metabolism and its impairment[8]. In the paper by Mohammadzadeh et al.[1], T allele in +276G/T SNP haplotype is highly associated with CAD in subjects with type 2 diabetes, but this linkage should be reappraised if related much more to diabetes rather than CAD. Association of T allele in the indicated SNP with CAD may be an indirect consequence of type 2 diabetes, as reported by others[9] or a direct marker for CAD affected patients[10]. The paper by Mohammadzadeh et al.[1] assesses data coming elsewhere from literature but raises important concerns about the suitability of ADIPOQ SNPs in diagnosing susceptibility to CAD and the relationship with plasma adiponectin level. In normal, non diabetic, normoglycemic subject, this relationship does not seem to work. Therefore the question is how much predictive this SNP haplotype may be to foresee metabolic syndrome and CAD onset risk in young health subjects? Maybe, the role of adiponectin in cardiovascular physiology depends on its ability to target adiponectin receptors and to negatively regulate obesity. Some authors reported in healthy volunteers an absence of correlation between circulating adiponectin levels and biochemical markers, particularly lipoproteins and suggested that SNP +276G>T was related to an independent effect on adiponectin levels and on lipoprotein metabolism[11]. On the contrary, adiponectin genetic variants and SNP +276G>T was associated with increasing susceptibility of type 2 diabetes and plasma glucose impairment[12]. The interesting study by Mohammadzadeh et al.[1] suggests that SNP of ADIPOQ +276G>T should be related to susceptibility to glucose metabolism, while indirectly to lipid metabolism and fat-related cardiovascular damage.
| S-EPMC4983672 | biostudies-literature
Project description:AimsThe present study aimed to reveal the relationship between single nucleotide polymorphism (SNP) of PNPLA3, TM6SF2, MBOAT7, GATAD2A, and STAT3 genes and metabolism-related fatty liver disease (MAFLD), so as to provide a research basis for further exploring the diagnosis and treatment of diseases at the molecular level.MethodsA total of 564 patients were included in the physical examination center of Xinjiang Karamay People's Hospital. They were divided into an MAFLD case group and a healthy control group. The whole blood DNA of each sample was extracted by a whole blood genomic DNA extraction kit, and the genotypes of PNPLA3 rs738409, MBOAT7 rs64173, STAT3 rs744166, TM6SF2 rs58542926, and GATAD2A rs4808199 were performed; after adjusting for confounding factors, the additive model, dominant model, and recessive model of each gene were analyzed by multivariate logistic regression.ResultsThe CC genotype of the PNPLA3 gene rs738409 and the TT genotype of the MBOAT7 gene rs64173 are risk factors in the occurrence of MAFLD. The AA genotype of the STAT3 gene rs744166 is a protective factor of MAFLD, while TM6SF2 rs58542926 and GATAD2A rs4808199 show no significant correlation with MAFLD.
| S-EPMC8831055 | biostudies-literature