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 (2= 14.4, P=0.0001) and showed some evidence for linkage to diabetes in 18 sibships from 9 French pedigrees (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.

1. DeFranzo, R.A., Lecture 1987: The Triumvirate: -Cell, Muscle, Liver: A Collusion Responsible for NIDDM. Diabetes 37, 667−687 (1988). | PubMed  | ISI | ChemPort |
2. Cherrington, A.D. et al. Insulin, glucagon and glucose as regulators of hepatic glucose uptake and production In vivo. Diabetes Met. Rev. 3, 307−332 (1987). | ChemPort |
3. Froguel, P. et al. Familial hyperglycaemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. New Engl. J. Med. 328, 697−702 (1993). | Article | PubMed  | ISI | ChemPort |
4. Froguel, P. et al. The glucokinase locus on chromosome 7 is closely linked to early-onset non-insulin-dependent diabetes mellitus. Nature 356, 162−164 (1992). | Article | PubMed  | ISI | ChemPort |
5. Steiner, D.F. et al. Lessons learned from molecular biology of insulin-gene mutations. Diabetes Care 13, 600−609 (1990). | PubMed  | ISI | ChemPort |
6. Van den Ouweland, J.M.W. et al. Mutation in mitochondrial tRNALeu (UUR) gene In a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet. 1, 368−371 (1993).
7. Taylor, S.I. Lessons from patients with mutations in the insulin-receptor gene. Diabetes 41, 1473−1490 (1992). | PubMed  | ISI | ChemPort |
8. Levebre, P., Paolisso, G. & Scheen, A. The role of glucagon in non-insulin-dependent (type 2) diabetes mellitus. In New directions In research and clinical works for obesity and diabetes mellitus: (eds Sakamoto, N., Angel, A. & Hotta, N.) 25−29 (Elsevier Science Publishers B.V., 1991).
9. Baron, A.D., Schaeffer, L., Shragg, P. & Koltermann, G.O. role of hyperglucagonemla in maintenance of increased rates of hepatic glucose output in Type II diabetics. Diabetes 36, 274−283 (1987). | PubMed  | ISI | ChemPort |
10. Segre, G.V. & Goldring, S.R. Receptors for secretln, calcitonin, parathyroid hormone (PTH)/PTH-related peptide, vasoactive intestinal peptide, glucagonlike peptide 1, growth hormone-releasing hormone, and glucagon belong to a newly discovered G-protein-linked receptor family. TEM 4, 309−314 (1993). | Article | ChemPort |
11. Jellnek, L.J. et al. Expression Cloning and Signaling Properties of the Rat Glucagon Receptor. Science 259, 1614−1616 (1993). | PubMed  |
12. Lok, S. et al. The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization. Gene 140, 203−209 (1994). | Article | PubMed  | ISI | ChemPort |
13. Vionnet, N. et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature (356, 721−22 (1992). | Article | PubMed  | ISI | ChemPort |
14. Bell, G.I. et al. Gene for non-insulin dependent diabetes mellitus (maturity onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc. natn. Acad. Sci. U.S.A 88, 1484−1488 (1991). | ChemPort |
15. Spielman, R.S., McGinnls, R.E. & Ewens, W.J. Transmission Test for Linkage Disequilibrium: The Insulin Gene Region and Insulin-dependent Diabetes Mellitus (IDDM). Am. J. hum. Genet. 52, 506−516 (1993). | PubMed  | ISI | ChemPort |
16. Juller, C. et al. Insulin-IGF 2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155−159 (1991). | Article | PubMed  | ISI | ChemPort |
17. Parsian, A. et al. Alcoholism and alleles of the human D2 dopamine receptor locus. Arch. Gen. Psychiatry 48, 655−663 (1991). | PubMed  | ISI | ChemPort |
18. Spiegel, A.M., Weinstein, L.S. & Shenker, A. Abnormalities in G Protein-coupled Signal Transduction Pathways In Human Disease. J. clln. Inv. 92, 1119−1125 (1993). | ChemPort |
19. Van Eyll, B., Lankat-Buttgerelt, B., Bode, H.P., Göke, R. & Göke, B. Cloning and functional expression of the GLP-1-Receptor from a human Insulinoma. Diabetes 43, (Suppl. 1) 178A (1994).
20. Van Schravendijk, C.F.H. et al. Pancreatic hormone receptors on islet cells. Endocrinology 117, 841−848 (1985). | PubMed  | ChemPort |
21. Samols, E., Marrl, G. & Marks, V. Promotion of insulin secretion by glucagon. Lancet 2, 415−416 (1965). | Article | ISI |
22. Gallus, G. & Garancinl, P. Dati epidemlologlci sul diabete mellito in Italia. Epldemiol. e Prevenz. 48-49, 55−58 (1991).
23. Linger, R.H., Aguilar-Parada, E., Mueller, W.A. & Eisentrant, A.M. Studies of pancreatic -cell function in normal and diabetic subjects. J. clln. Invest. 49, 837−845 (1970).
24. Raskin, P. & Unger, H. Hyperglucagonemia and its supression, importance in the metabolic control of diabetes. New Engl. J. Med. 290, 433−436 (1978).
25. Vionnet, N., Passa, P. & Froguel, P. Prevalence of mitochondrial gene mutations in families with diabetes mellitus. Lancet 342, 1429−1430 (1993). | Article | PubMed  | ISI | ChemPort |
26. Elston, R.C., Bailey-Wilson, J.E., Bonney, G.E., Keats, B.J. & Wilson, A.F. S.A.G.E. — A package of computer programs to perform statistical analysis in genetic epidemiology. Presented at the 7th international congress of human genetics, Berlin, Germany, September 22−26 (1986).
27. Ho, S.N., Hunt, H.D., Horton, R.M., Pullen, J.K. & Pease, L.R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77, 51−59 (1989). | Article | PubMed  | ISI | ChemPort |

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