Human glucokinase gene

Isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus

M. Stoffel, P. H. Froguel, J. Takeda, H. Zouali, N. Vionnet, S. Nishi, I. T. Weber, R. W. Harrison, S. J. Pilkis, S. Lesage, M. Vaxillaire, G. Velho, F. Sun, F. Iris, P. H. Passa, David Cohen, G. I. Bell

Research output: Contribution to journalArticle

205 Citations (Scopus)

Abstract

DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in ≈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 β-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 β-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. (.

Original languageEnglish (US)
Pages (from-to)7698-7702
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number16
StatePublished - 1992
Externally publishedYes

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Glucokinase
Missense Mutation
Type 2 Diabetes Mellitus
Mutation
Genes
Exons
Glucose
Hexokinase
Glucose Intolerance
Nonsense Codon
Carbohydrate Metabolism
Hepatocytes
Adenosine Triphosphate
Yeasts
DNA
Proteins

Keywords

  • Chromosome 7
  • Glucose
  • Metabolism
  • Phosphorylation
  • Structure-function

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Human glucokinase gene : Isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. / Stoffel, M.; Froguel, P. H.; Takeda, J.; Zouali, H.; Vionnet, N.; Nishi, S.; Weber, I. T.; Harrison, R. W.; Pilkis, S. J.; Lesage, S.; Vaxillaire, M.; Velho, G.; Sun, F.; Iris, F.; Passa, P. H.; Cohen, David; Bell, G. I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 16, 1992, p. 7698-7702.

Research output: Contribution to journalArticle

Stoffel, M, Froguel, PH, Takeda, J, Zouali, H, Vionnet, N, Nishi, S, Weber, IT, Harrison, RW, Pilkis, SJ, Lesage, S, Vaxillaire, M, Velho, G, Sun, F, Iris, F, Passa, PH, Cohen, D & Bell, GI 1992, 'Human glucokinase gene: Isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus', Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 16, pp. 7698-7702.
Stoffel, M. ; Froguel, P. H. ; Takeda, J. ; Zouali, H. ; Vionnet, N. ; Nishi, S. ; Weber, I. T. ; Harrison, R. W. ; Pilkis, S. J. ; Lesage, S. ; Vaxillaire, M. ; Velho, G. ; Sun, F. ; Iris, F. ; Passa, P. H. ; Cohen, David ; Bell, G. I. / Human glucokinase gene : Isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. In: Proceedings of the National Academy of Sciences of the United States of America. 1992 ; Vol. 89, No. 16. pp. 7698-7702.
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abstract = "DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in ≈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 β-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 β-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. (.",
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T2 - Isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus

AU - Stoffel, M.

AU - Froguel, P. H.

AU - Takeda, J.

AU - Zouali, H.

AU - Vionnet, N.

AU - Nishi, S.

AU - Weber, I. T.

AU - Harrison, R. W.

AU - Pilkis, S. J.

AU - Lesage, S.

AU - Vaxillaire, M.

AU - Velho, G.

AU - Sun, F.

AU - Iris, F.

AU - Passa, P. H.

AU - Cohen, David

AU - Bell, G. I.

PY - 1992

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N2 - DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in ≈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 β-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 β-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. (.

AB - DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in ≈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 β-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 β-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. (.

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