DESCRIPTION OF A 2ND MICROSATELLITE MARKER AND LINKAGE ANALYSIS OF THE MUSCLE GLYCOGEN-SYNTHASE LOCUS IN FAMILIAL NIDDM

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by im paired insulin-stimulated glucose uptake into glycogen. Both biochemic al and genetic data have implicated glycogen synthase as a candidate f or the genetic predisposition to diabetes. To test this hypothesis, we isolated cosmid clones containing genomic DNA for the glycogen syntha se (GSY) gene and identified a region of 20 GT repeat units in a clone that extended 15 kilobases 3' to the gene. This region was highly pol ymorphic with nine alleles (heterozygosity 0.74). With the use of this polymorphism, the GSY was mapped on chromosome 19q between markers D1 9S217 and D19S210 and at Theta = 0.036 from the histidine-rich calcium -binding protein (HRC) locus. Linkage to GSY was rejected under multip le models with logarithm of odds (LOD) scores of -1.36 to -5.22, In co ntrast, we could not reject linkage under dominant and intermediate (a dditive) models for the HRC locus (maximum LOD scores 1.51 and 1.54), despite the close proximity to GSY. Multipoint analysis of NIDDM versu s GSY and HRC placed the putative diabetes locus centromeric to HRC an d away from GSY. Furthermore, analysis of the previously associated Xb a I polymorphism suggested neither linkage nor sib-pair sharing. We co nclude that mutations of the GSY gene are unlikely to play a major rol e in the predisposition to NIDDM in our families. However, we cannot e xclude a modifying role in a polygenic disorder or an important role i n some families. The moderately positive LOD scores near the HRC locus suggest a need for evaluation of this region in additional NIDDM fami lies.