Studies involving surveys of single nucleotide polymorphisms (SNPs) throughout the entire human genome have recently detected an association of a SNP in the first exon of the JAZF1 gene and individuals with type 2 diabetes. The biologic basis of this association is unknown. Moreover, little is known about the function of this gene in general. Its protein product is present in most human cells and is located in both the cytoplasm and the nucleus. The 5'end of JAZF1 is part of a gene fusion present in endometrial stromal tumors, and pre-mRNA transcribed from the gene participates in trans-splicing with pre-mRNA of a second gene within normal endometrial stromal cells. One report has found that JAZF1 protein co-precipitates with an orphan nuclear receptor, NR2C2. Whole genome association studies similar to those involving type 2 diabetes have found that a JAZF1 SNP physically linked closely to that correlated with type 2 diabetes is commonly found in people of increased height and a separate SNP in intron 2, outside the area of linkage disequilibrium with the intron 1 SNPs, is associated with decreased risk of prostate cancer. In preliminary studies, we have shown that the SNP associated with type 2 diabetes leads to increased pre-mRNA from the JAZF1 gene in fibroblasts and tonsil tissue. Seemingly consistent with that finding, our studies have also shown that knockout mice lacking functional JAZF1 have low basal serum insulin levels and a hypoglycemic response to glucose challenge. In research proposed in this application, we will further characterize in lymphocytes and various human tissues the altered expression of JAZF1 alleles containing the SNP associated with type 2 diabetes. We will conduct hyperinsulinemic-euglycemic and hyperglycemic clamp experiments on the JAZF-/- mice to determine if the effect already detected on insulin and glucose metabolism is related to changes in insulin sensitivity and/or insulin secretion from pancreatic beta cells, compared to wild type mice. We will also determine whether expression of JAZF1 transgenes inserted into cultured cells alters insulin sensitivity and/or insulin secretion. Finally, we will identify proteins to which JAZF1 binds and changes in levels of RNA induced by JAZF1. Taken together, these studies will greatly advance understanding of how JAZF1 in particular and SNP variants in general may influence susceptibility to type 2 diabetes and other diseases.
The research proposed in this application is relevant to whole genome association (WGA) studies of inherited risk of diseases and constitutional traits;mechanisms by which single nucleotide polymorphisms (SNP) are associated with altered risk of disease;polygenic risks of disease;genetic susceptibility to type 2 diabetes;and the function of the JAZF1 gene in normal and dysfunctional cells.