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.
Hager
J
J
CNRS EP 10, INSERM U358, Hôpital Saint-Louis, Paris, France.
Hansen
L
L
Vaisse
C
C
Vionnet
N
N
Philippi
A
A
Poller
W
W
Velho
G
G
Carcassi
C
C
Contu
L
L
Julier
C
C
D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D005934:Glucagon / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D018027:Receptors, Glucagon; D005934:Glucagon