title: Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees.
abstract: 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.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Hu
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Luo
authors.forename: Xiang
authors.initials: X
authors.lastname: Mao
authors.forename: Xiujun
authors.initials: X
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Lu
authors.initials: L
authors.lastname: Guan
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Jianwei
authors.initials: J
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Long
authors.forename: Xiangxun
authors.initials: X
authors.lastname: Zhang
authors.forename: Haoming
authors.initials: H
authors.lastname: Tian
mesh_terms: D001483:Base Sequence; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005820:Genetic Testing; D006801:Humans; D015228:Hypertriglyceridemia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D008071:Lipoprotein Lipase