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 1 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 1 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

Insulin resistance caused by lipotoxicity is related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice

“…Our previous systemic review also showed significant correlation between HTG and T2DM in LPL Asn291Ser variant carriers [2]. Through further study of type 2 diabetic pedigrees in a Chinese population, we reported three novel mutations of LPL gene, Lys312insC, Thr361insA, and double mutation Lys312insC þ Asn291Ser, all of which negatively affected LPL activity and were clinically associated with HTG [3].…”

“…Since we have found the genetic variants contributed to LPL deficiency and the observed HTG in T2DM pedigrees in previous studies [2,3], we use LPLþ/À mice to be the animal model for inherited HTG. In accordance with the standard for HTG animal model, LPLþ/À mice in our study display decreased LPL expression and activity, and increased plasma TG level.…”

The common biological basis for common complex diseases: evidence from lipoprotein lipase gene

“…Their result is supported by Groenemeijer et al 16 and double mutations Lys312insC+Asn291Ser, were clinically associated with hypertriglyceridemia, which was further confirmed by the mutagenesis with significantly reduced LPL activity (Po0.01) and expression studies. 19 Yang et al 20 found that two SNPs HindIII (rs320) and HinfI (rs328) at LPL were associated with cholesterol levels (P¼0.0178 and P¼0.0088, respectively) in Chinese cohort.…”

Relationship of lipoprotein lipase gene variants and fasting triglyceride levels in a pediatric population: TheCASPIAN-III study

“…[20][21][22][23] To date, approximately 143 different mutations have been found in the human LPL gene, 90% of which occur in the coding regions and affect LPL functions through catalytic activity, dimerization, secretion, and heparin bonding. 24 Some previous studies have shown that SNPs located in the LPL gene are associated with TG levels. It is also documented that rs2083637 and rs10096633 are related to TG levels.…”