Genetic analysis of type 1 diabetes

The research in this thesis exploits the utility of mouse genetics in the study of type 1 diabetes to locate and characterise a susceptibility locus, Iddl8, in a spontaneous model of the human disease, the nonobese diabetic (NOD) mouse. The NOD mouse shares almost all of the main features of type 1 diabetes, which in most cases appears to be an autoimmune disease of the insulin-producing cells of the pancreas, resulting in irreversible insulin-deficiency. I refined the Idd18 interval, now designated Idd18.1, from 5 Mb to 700 kb. Vav3, which encodes a protein with known function in the immune system, is the only complete gene in Idd18.1. Therefore, Vav3 is probably the causative gene for Idd18.1. To begin to identify the aetiological variant(s) in Vav3, the coding regions, regions containing splice sites, and regions potentially encompassing additional regulatory regions of the gene were sequenced using NOD genomic DNA and the sequence was compared to the diabetes-resistant C57BL/6 (B6) genomic sequence. In addition. I identified six putative splice variants of Vav3, and three of these were observed by reverse transcriptase PCR in RNA from the tissues tested. Although no polymorphisms were identified in the coding sequence of any of the known, and novel, Vav3 isoform transcripts, several polymorphisms were found in the introns and 5’ and 3’ untranslated regions, which could affect transcription or splicing. However, to date, no expression or splicing differnces have been ascertained when comparing tissues obtained from NOD and NOD.B6 Idd18 congenic ice. I also mapped a new susceptibility locus adjacent to Idd18.1, designated Idd18.2. The Idd18.2 interval is 7.4 Mb and contains approximately 118 annotated genes, several of which have a role in the immune system.EThOS - Electronic Theses Online ServiceGBUnited Kingdo