MOLECULAR ANALYSIS OF INSULIN-RECEPTOR GENE IN WERNERS-SYNDROME

Werner's syndrome is characterized by premature aging and frequent imp aired glucose tolerance or overt diabetes, Insulin resistance may play an important role and may be caused by a post-receptor defect or dysf unctional insulin receptor. The present study was undertaken to invest igate the insulin receptor gene mutation in Werner's syndrome. The gen omic DNAs were obtained from four patients with Werner's syndrome. Exo ns 2-22 of the insulin receptor gene except exon 1 were amplified from genomic DNA by the polymerase chain reaction and screened for nucleot ide variation by examining for single-stranded conformational polymorp hisms. There were no nucleotide variations in exons 2,4 --> 7,9 and 12 --> 22. Variants were thus found in exons 3, 8, 10 and 11 and each we re sequenced. The variant in exon 8 was due to a silent polymorphism ( GAT --> GAC/T, Asp(519)) and other variants in exons 3, 10 and 11 were caused by nucleotide substitutions in introns, These results suggest that the patients with Werner's syndrome express normal insulin recept ors and that the primary genetic lesion for insulin resistance is not in the insulin receptor gene. Insulin resistance in Werner's syndrome is thus likely by a post-receptor defect.