Role of the single nucleotide polymorphism rs7903146 of TCF7L2 in inducing nonsense-mediated decay

Abstract

BackgroundThe single nucleotide polymorphism (SNP) rs7903146 (C/T), located in intron 4 of the transcription factor 7-like 2 gene (TCF7L2), has been associated with an increased risk of developing Type 2 Diabetes, although the molecular mechanism remain elusive. The TCF7L2 gene is alternatively spliced but an association between genotype and splice variants has not been shown convincingly. We hypothesized that a yet unknown extra exon, containing either the C or T genotype of the SNP rs7903146, could introduce a premature stop codon and consequently result in nonsense-mediated decay (NMD).FindingsRunning the sequences C and T of the SNP region in different servers we found that the two alleles could display differential recognition by splicing factors. The C variant showed the possible inclusion of an unknown exon. This unknown exon contained a stop codon and thus could induce NMD. We then determined that the splicing pattern in isolated mouse islets and MIN6 cells was similar to that in human pancreatic islets. Therefore, we used MIN6 cells to study the splicing of human intron 4: two mini-genes of intron 4 containing either the C/C genotype or the T/T genotype were transfected into MIN6 cells. Our constructs were spliced normally, excluding intron 4, but we did not observe the presence of an extra exon with either construct.ConclusionsWe found that an extra exon could theoretically exist, although we were not able to capture it in our model. A better model is needed to determine whether a theoretical extra exon can induce NMD.

A HuGE Review and Meta-Analyses of Genetic Associations in New Onset Diabetes after Kidney Transplantation

“…It may affect blood glucose homeostasis by altering levels of glucagon-like peptide 1 in the gut, or it may decrease insulin secretion via the pancreatic beta, adipose or liver cells [ 54 ]. rs7903146 is located in an intron; a non-protein coding region of the gene [ 55 ]. There is no obvious mechanism by which a mutation at this locus could affect NODAT or T2D development, however the variant rs7903146 may either be in linkage disequilibrium with a causal allele or may itself influence gene expression through regulatory mechanisms.…”

Intronic SNPs and Genetic Diseases: A Review

“…This SNP leading to alters the mRNA reading frame, produce 87 amino acids and results in a premature stop codon [69]. Intron 4 SNPs rs7903146 existing in the transcription factor 7-like 2 gene (TCF7L2), both the C or T genotype of this SNP could produce a premature stop codon and shows the strongest genetic factor associated with type 2 diabetes [70].…”

Prevalence of the rs7903146C>T polymorphism in TCF7L2 gene for prediction of type 2 diabetes risk among Iranians of different ethnicities

“…A strong association was identified between T2D and a single nucleotide rs7903146C>T polymorphism, located within intron 4 of the TCF7L2 gene. 4 , 5 TCF7L2 gene consists of 17 exons and is located on chromosome 10q25.3, where the rs7903146C>T polymorphism is the most important of these improved variants with negative effects on metabolism. Certain variants of TCF7L2 gene increase the risk of T2D and reduce insulin secretion.…”