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

被引:81
作者
Triggs-Raine, BL
Kirkpatrick, RD
Kelly, SL
Norquay, LD
Cattini, PA
Yamagata, K
Hanley, AJG
Zinman, B
Harris, SB
Barrett, PH
Hegele, RA
机构
[1] John P Robarts Res Inst, London, ON N6A 5K8, Canada
[2] Univ Manitoba, Dept Biochem & Mol Genet, Winnipeg, MB R3E 0W3, Canada
[3] Univ Manitoba, Dept Physiol, Winnipeg, MB R3E 0W3, Canada
[4] Osaka Univ, Dept Internal Med & Mol Sci, Suita, Osaka 5650871, Japan
[5] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada
[6] Univ Western Ontario, Thames Valley Family Practice Res Unit, London, ON N6G 4X8, Canada
[7] Univ Western Australia, Dept Med, Perth, WA 6847, Australia
[8] Western Australian Inst Med Res, Perth, WA 6847, Australia
关键词
D O I
10.1073/pnas.062059799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-1alpha (HNF-1alpha), was associated with Oji-Cree type 2 diabetes and was found in approximate to40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1alpha to activate transcription by approximate to50%, 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 approximate to 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.
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收藏
页码:4614 / 4619
页数:6
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