We have identified a novel type of early-onset, autosomal dominant type 2 diabetes that is distinct from known forms of MODY, being characterized by the presence of insulin-resistance rather than an isolated insulin secretion defect. The autosomal dominant pattern of inheritance and the young age at onset in affected families make the goal of cloning the genes involved in this form of type 2 diabetes particularly feasible. In a genome screen of 21 large families with this type of diabetes, we have identified two putative disease loci on chromosomes 8p23 and 2q37. Through the analysis of recombinants, we were able to narrow the 8p23 locus to 2.0 Mb and to exclude the calpain 10 gene as the diabetes gene at 2q37. In this renewal application, we propose to refine this mapping and positionally clone the genes underlying these two diabetes loci. Our specific goals are: 1. To narrow the critical intervals on 8p23 and 2q37. We will study 60 new large families with early-onset autosomal dominant type 2 diabetes to identify new recombination events in the critical intervals. Informative microsatellite and SNP markers will be typed to map recombination events as accurately as possible. 2. To clone the genes underlying these loci. We will identify positional candidate genes in the narrowed critical intervals and will sequence them in probands from linked families to find the putative DNA sequence difference(s) causing diabetes in these families. 3. To find the genes responsible for diabetes in families not linked to 8p23 or 2q37. We will pursue such families by studying their linkage to other chromosomal regions that also emerged from the genome screen (19q12, 11p15, 1q43), and by screening novel candidate genes involved in insulin action. Identification of genes that are responsible for early-onset type 2 diabetes will have a profound impact on research on insulin action. It will provide critical knowledge for identifying those cellular pathways that are involved in the development of insulin-resistance - with possible implications for the etiology of more common forms of type 2 diabetes and the development of drugs to treat insulin resistance. ? ?
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