HNF-1α G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community

• Barbara L. Triggs-Raine

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Robert D. Kirkpatrick

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Sherrie L. Kelly

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Lisa D. Norquay

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Peter A. Cattini

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Kazuya Yamagata

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Anthony J. G. Hanley

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Bernard Zinman

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Stewart B. Harris

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• P. Hugh Barrett

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

• Robert A. Hegele

  Departments of Biochemistry and Medical Genetics and Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3; Department of Internal Medicine and Molecular Science, Osaka University, Osaka 565-0871, Japan; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario, London, ON, Canada N6G 4X8; Department of Medicine, University of Western Australia and Western...

抄録

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A , which encodes hepatic nuclear factor-1α (HNF-1α), was associated with Oji-Cree type 2 diabetes and was found in ≈40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1α to activate transcription by ≈50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant negative effect of the mutant protein. The impact of the G319S mutation at the population level was assessed by classifying subjects with type 2 diabetes according to HNF1A genotype and plotting the cumulative age of onset of diabetes. Disease onset was modeled satisfactorily by two-parameter sigmoidal functions for all diabetic subjects and all three HNF1A genotypes. Pairwise statistical comparisons showed significant between-genotype differences in t 50 (all P < 0.00001), corresponding to the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by ≈7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for HNF1A G319S provides a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health dilemma. The findings also show that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 99 (7), 4614-4619, 2002-03-19

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361981470104171520
• NII論文ID: 30016224637
• DOI: 10.1073/pnas.062059799
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.062059799
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