SEARCH FOR A 3RD SUSCEPTIBILITY GENE FOR MATURITY-ONSET DIABETES OF THE YOUNG - STUDIES WITH 11 CANDIDATE GENES

Maturity-onset diabetes of the young (MODY) is a model for genetic stu dies of non-insulin-dependent diabetes mellitus. We have identified 15 MODY families in which diabetes is not the result of mutations in the glucokinase gene. This cohort of families will be useful for identify ing other diabetes-susceptibility genes. Nine other candidate genes po tentially implicated in insulin secretion or insulin action have been tested for linkage with MODY in these families, including glucokinase regulatory protein, hexokinase II, insulin receptor substrate 1, fatty acid-binding protein 2, glucagon-like peptide-1 receptor, apolipoprot ein C-II, glycogen synthase, adenosine deaminase (a marker for the MOD Y gene on chromosome 20), and phosphoenolpyruvate carboxykinase. None of these loci showed evidence for linkage with MODY, implying that mut ations in these genes do not make a major genetic contribution to the development of MODY. In addition to these linkage analyses, one or two affected subjects from each family were screened for the presence of the A to G mutation at nucleotide 3,243 of the mitochondrial tRNALeu(U UR) gene. This mutation was not found in any of these subjects. Finall y, we report the localization of the gene encoding the regulatory prot ein of glucokinase to chromosome 2, band p22.3 and the identification of a restriction fragment length polymorphism at this locus.