MISSENSE MUTATION OF AMYLIN GENE (S20G) IN JAPANESE NIDDM PATIENTS

Many studies suggest that amylin, which is cosecreted with insulin hom islet beta-cells, is a biologically active peptide and modulates plas ma glucose levels. We therefore scanned the amylin gene for mutations in 294 Japanese NIDDM patients by single-strand conformational polymor phism, and we found a single heterozygous missense mutation (Ser-->Gly at position 20: S20G mutation) in 12 NIDDM patients (frequency 4.1%). None of the 187 nondiabetic subjects or 59 IDDM patients had the muta tion. Of 12 patients carrying the mutation, 8 were diagnosed as having NIDDM at a relatively early age (less than or equal to 35 years), and they had severe diabetes and strong family histories of late-onset NI DDM. On the other hand, the remaining four patients were diagnosed as having NIDDM after age 51, and they had mild diabetes without family h istories of diabetes. In high-performance liquid chromatography analys is, a small amount (16%) of amylin immunoreactivity appeared in the po sition corresponding to normal amylin and a much larger amount (84%) a ppeared in the position corresponding to mutant amylin. These findings suggest that the S20G mutation of the amylin gene may play a partial role in the pathogenesis of early-onset NIDDM in the Japanese populati on and may also provide an important model to investigate the true phy siological action of amylin.