title: Pathogenic mutations of the lipoprotein lipase gene in Chinese patients with hypertriglyceridemic type 2 diabetes.
abstract: Elevated plasma triglyceride and nonesterified fatty acid concentrations may cause insulin resistance. Lipoprotein lipase (LPL) is a rate-determining enzyme in lipid metabolism. To investigate the role of the LPL gene in Chinese patients with hypertriglyceridemic type 2 diabetes, 277 patients with type 2 diabetes and 241 healthy control subjects were recruited and screened for sequence changes in the LPL gene by PCR, SSCP, restriction analysis and direct DNA sequencing. Ten mutations were identified: four missense mutations, Ala71Thr, Val181Ile, Gly188Glu and Glu242Lys; one nonsense mutation Ser447Ter; and five silent mutations. Ser447Ter was found in both patients and controls with no significant difference in frequency. The four missense mutations were located in the highly conserved exon 3, 5, and 6 regions and in highly conserved amino acid sites. They led to reduced LPL mass and enzyme activities in both post-heparin plasma and in vitro expression. The modeled structures displayed major differences between the mutant and wildtype molecules. These results indicated that the four missense mutations lead to LPL deficiency and subsequent hypertriglyceridemia. Based on our study and published data, a putative pathogenic pathway was suggested: LPL enzyme deficiency causes elevated plasma triglyceride level and subsequent insulin resistance; both increased free fatty acids and insulin resistance promote gluconeogenesis and hyperglycaemia, a vicious circle leading to type 2 diabetes.
authors.affiliation: Department of Chemical Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Chi-Pui
authors.initials: CP
authors.lastname: Pang
authors.forename: Man-Wo
authors.initials: MW
authors.lastname: Tsang
authors.forename: Ching-Wan
authors.initials: CW
authors.lastname: Lam
authors.forename: Priscilla M K
authors.initials: PM
authors.lastname: Poon
authors.forename: Lisa Y S
authors.initials: LY
authors.lastname: Chan
authors.forename: Xiang-Qian
authors.initials: XQ
authors.lastname: Wu
authors.forename: Brian
authors.initials: B
authors.lastname: Tomlinson
authors.forename: Larry
authors.initials: L
authors.lastname: Baum
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002681:China; D002522:Chlorocebus aethiops; D030562:Databases, Protein; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D005260:Female; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000201:enzymology / Q000235:genetics; D015228:Hypertriglyceridemia / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics*; D009679:Nuclear Family
chemical_list: D008071:Lipoprotein Lipase