Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ

One of the loci responsible for genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) is the insulin-linked polymorphic region (ILPR, also known as IDDM2). This polymorphic G-rich minisatellite, located in the promoter region of the human insulin gene, comprises a variable number of tandemly repeating sequences related to ACAGGGGTGTGGGG. An interesting characteristic of the ILPR is its ability to form unusual DNA structures in vitro. presumably through formation of C-quartets. This ability to form C-quartets raises the intriguing possibility that transcriptional activity of the insulin gene may in fact be influenced by the quaternary DNA topology of the ILPR. We now show that single nucleotide differences in the ILPR known to affect insulin transcription are correlated with ability to form unusual DNA structures. Through the design and testing of two high transcriptional activity ILPR repeats, we demonstrate that both inter- and intramolecular G-quartet formation in the ILPR can influence transcriptional activity of the human insulin gene, and thus, may contribute to that portion of diabetes susceptibility attributed to the IDDM2 locus.