Group members

The TCF7L2 & Wnt Action Group

The transcription factor TCF7L2 (T-cell factor 7-like 2) is uncontested as the most important type 2-diabetes gene in populations of African, Asian and European descent. A genetic variation (rs7903146) located within intron 4 of the TCF7L2 gene is suggested to be the functional variant.

TCF7L2-dependent diabetes presents with reduced insulin production and also impaired action of the incretin hormone glucagon-like peptide 1 (GLP1) that stimulates output from the pancreatic beta-cell. These facts aside, a unifying hypothesis on the pathogenesis of TCF7L2-dependent diabetes is missing. For example, TCF7L2 splicing is complex and it is not known which splice vaiants and protein isoforms that are relevant for the disease. Furthermore, TCF7L2 is a transcription factor and binds to a vast number of genes, but it is unclear which ones matter for diabetes.

We aim to understand the mechanisms behind TCF7L2-dependent diabetes and to sugggest approaches to treat this dysfunction. Based on clinical phenotypes and data on TCF7L2 expression, we focus on identifying the TCF7L2 splice pattern and functional role of the different protein isoforms in pancreatic islet cells. We have recently shown that the beta-cell has high incorporation of the variable exon 4, and that this relates to the degree of impaired glucose tolerance in risk carriers. If we can validate that elevated expression of exon 4 causes diabetes, then this could be corrected by exon skipping gene therapy as currently in clinical trials for other diseases.

Figure 1. Gene and mRNA structure of TCF7L2. (top panel). The gene structure is outlined displaying the 17 exons with the location of the rs7903146 polymorphism indicated. (middle panel) The exon structure shown schematically with exon numbering. alternative exons are coloured and important alternative splice sites are marked by hatching. Sequences encoding important binding sites are indicated. Stop codon usage for "short", "medium" and "long" TCF7L2 protein isoforms is shown by boxed S, M and L, respectively. (bottom panel) The four predominating splice variants expressed in human pancreatic islets are shown.


Zhou Y, Zhang E, Berggreen C, Jing X, Osmark P, Lang S, Cilio C.M., Göransson O., Groop L., Renström E., Hansson O. "Survival of pancreatic beta-cells is partly controlled by a TCF7L2 - p53 - p53INP1 dependent pathway", 2011, Hum Mol Genet, Jan 1;21(1):196-207

Hansson O., Zhou Y., Renström E., Osmark P. "Molecular function of TCF7L2 - consequences of TCF7L2 splicing for molecular function and risk for type 2-diabetes" 2010, Current Diabetes Reports, Dec; 10(6):444-51

Prokunina-Olsson L., Welch C., Hansson O., Adhikari N., Scott L., Usher N., Tong M., Sprau A., Swift A., Bonnycastle L., He K., Erdos M., Saxena R., Harmon B., Kotova O., Hoffmann E., Altshuler D., Groop L., Boehnke M., Collins F. and Hall J.L., "Tissue-specific Alternative Splicing of TCF7L2: Possible Relationship to Risk of Type 2 Diabetes", 2009, Hum Mol Genet, Oct 15;18(20(:3795-804

[Osmark P., Hansson O.], Jonsson A., Rönn T., Renström E., "Unique splicing pattern of the TCF7L2 gene in human pancreatic isets" 2009, Diabetologia, May;52(5):850-4, [Shared first authorship]

Last updated: January 23, 2012
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