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Papers In Press, published online ahead of print August 1, 2007
J. Lipid Res., doi:10.1194/jlr.M600382-JLR200

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Journal of Lipid Research, Vol. 48, 1681-1688, August 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees

Yaomin Hu^1,*, Yan Ren^*, Robert Z. Luo, Xiang Mao, Xiujun Li^*, Xu Cao^*, Lu Guan^*, Xiang Chen^*, Jianwei Li^*, Yang Long^*, Xiangxun Zhang^* and Haoming Tian^2,*,**

^* Division of Endocrinology, Department of Internal Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
^** State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three tables.

Published, JLR Papers in Press, May 2, 2007.

¹ Present address of Y. Hu: Division of Endocrinology, Department of Internal Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 1630 Dongfang Road, Shanghai 200127, China.

² To whom correspondence should be addressed. e-mail: tianhaoming2006{at}yahoo.com

Increased plasma triglyceride and free fatty acid levels are frequently associated with type 2 diabetes mellitus (T2DM). To test the hypothesis that LPL gene mutations contribute to the hypertriglyceridemia observed in members of T2DM pedigrees, we screened the LPL gene in 53 hypertriglyceridemic members of 26 families. Four known and three novel mutations were identified. All three novel mutations, Lys312insC, Thr361insA, and double mutation Lys312insC + Asn291Ser, are clinically associated with hypertriglyceridemia. In vitro mutagenesis and expression studies confirm that these variants are associated with a significant reduction in LPL activity. The modeled structures displaying the Lys312insC and Thr361insA mutations showed loss of the activity-related C-terminal domain in the LPL protein. Another novel double mutation, Lys312insC + Asn291Ser, resulted in the loss of the catalytic ability of LPL attributable to the complete loss of the C-terminal domain and alteration in the heparin association site. Thus, these novel mutations of the LPL gene contribute to the hypertriglyceridemia observed in members of type 2 diabetic pedigrees.

Supplementary key words mutation • function • molecular modeling

Abbreviations: DHPLC, denaturing high-performance liquid chromatography; SSCP, single-strand conformation polymorphism; T2DM, type 2 diabetes mellitus; TG, triglyceride

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