出版社：American Society for Biochemistry and Molecular Biology
摘要：Increased plasma triglyceride and free fatty acid levels arefrequently associated with type 2 diabetes mellitus (T2DM).To test the hypothesis that LPL gene mutations contribute tothe hypertriglyceridemia observed in members of T2DM pedigrees,we screened the LPL gene in 53 hypertriglyceridemic membersof 26 families. Four known and three novel mutations were identified.All three novel mutations, Lys312insC, Thr361insA, and doublemutation Lys312insC + Asn291Ser, are clinically associated withhypertriglyceridemia. In vitro mutagenesis and expression studiesconfirm that these variants are associated with a significantreduction in LPL activity. The modeled structures displayingthe Lys312insC and Thr361insA mutations showed loss of the activity-relatedC-terminal domain in the LPL protein. Another novel double mutation,Lys312insC + Asn291Ser, resulted in the loss of the catalyticability of LPL attributable to the complete loss of the C-terminaldomain and alteration in the heparin association site. Thus,these novel mutations of the LPL gene contribute to the hypertriglyceridemiaobserved 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
