RNA Metabolism in Myotonic Dystrophy Patient Muscle Shows Decreased Insulin Receptor RNA and Protein Consistent with Abnormal Insulin Resistance

Myotonic dystrophy is a dominantly inherited clinically variable multisystemic disorder, and has been found to be caused by heterozygosity for a trinucleotide repeat expan-sion mutation in the 3 9 untranslated region of a protein ki-nase gene (DM kinase). The mechanisms by which the ex-panded repeat in DNA results in a dominant biochemical defect and the varied clinical phenotype, is not known. We have recently proposed a model where disease pathogenesis may occur at the RNA level in myotonic dystrophy: the mu-tant DM kinase RNA with the expansion mutation may dis-rupt cellular RNA metabolism in some general manner, as evidenced by defects in RNA processing of the normal DM kinase gene in heterozygous patients (dominant negative RNA mutation). Here we further test this hypothesis by measur-ing RNA metabolism of other genes in patient muscle biop-sies (nine adult onset myotonic dystrophy patients, two con-genital muscular dystrophy patients, four normal controls, and four myopathic controls). We focused on the insulin re-ceptor gene because of the documented insulin resistance of DM patients. We show that there is a significant decrease in insulin receptor RNA in both total RNA and RNA poly