A MISSENSE MUTATION IN THE GLUCAGON RECEPTOR GENE IS ASSOCIATED WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Non-insulin-dependent diabetes mellitus (NIDDM) affects about 5% of the world population. The disease presents a polygenic mode of inheritance, but mechanisms and genes involved in late-onset NIDDM are largely unknown. We report the association of a single heterozygous Gly to Ser missense mutation in the glucagon receptor gene with late-onset NIDDM. This mutation was highly associated with NIDDM in a pooled set of French and Sardinian patients (chi(2)=14.4, P=0.0001) and showed some evidence for linkage to diabetes in 18 sibships from 9 French pedigrees (chi(2)=6.63, P<0.01). Receptor binding studies using cultured cells expressing the Gly40Ser mutation demonstrate that this mutation results in a receptor which binds glucagon with a three-fold lower affinity compared to the wild type receptor.