Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus
| Autor: | Philippe Froguel, H Zouali, S Lesage, Markus Stoffel, J. Takeda, Robert W. Harrison, S Nishi, Irene T. Weber, Nathalie Vionnet, S J Pilkis |
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| Rok vydání: | 1992 |
| Předmět: |
Adult
Male Models Molecular medicine.medical_specialty Protein Conformation Molecular Sequence Data Restriction Mapping Nonsense mutation MODY 2 Biology medicine.disease_cause Polymerase Chain Reaction chemistry.chemical_compound Internal medicine Glucokinase medicine Humans Missense mutation Family Amino Acid Sequence Child Genetics Genomic Library Hexokinase Mutation Polymorphism Genetic Multidisciplinary Base Sequence Age Factors Type 2 Diabetes Mellitus DNA Exons medicine.disease Introns Pedigree Glucose binding Endocrinology Diabetes Mellitus Type 2 Oligodeoxyribonucleotides chemistry Female Research Article |
| Zdroj: | Proceedings of the National Academy of Sciences. 89:7698-7702 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.89.16.7698 |
| Popis: | DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. |
| Databáze: | OpenAIRE |
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