Genetic and functional studies of the LMF1 gene in Thai patients with severe hypertriglyceridemia

Wanee Plengpanich,Suwanna Muanpetch,Supannika Charoen,Arunrat Kiateprungvej,Weerapan Khovidhunkit

doi:10.1016/j.ymgmr.2020.100576

Wanee Plengpanich, Suwanna Muanpetch + Show 3 more

Open Access

https://doi.org/10.1016/j.ymgmr.2020.100576

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Abstract

Severe hypertriglyceridemia (HTG) due to chylomicronemia is associated with acute pancreatitis and is related to genetic disturbances in several proteins involved in triglyceride (TG) metabolism. Lipase maturation factor 1 (LMF1) is a protein essential for the maturation of lipoprotein lipase (LPL). In this study, we examined the genetic spectrum of the LMF1 gene among subjects with severe HTG and investigated the functional significance of 6 genetic variants in vitro. All 11 exons of the LMF1 gene were sequenced in 101 Thai subjects with severe HTG. For an in vitro study, we performed site-directed mutagenesis, transient expression in cld cells, and measured LPL protein and LPL activity. We identified 2 common variants [p.(Gly36Asp) and p.(Pro562Arg)] and 12 rare variants [p.(Thr143Met), p.(Asn249Ser), p.(Ala287Val), p.(Met346Val), p.(Thr395Ile), p.(Gly410Arg), p.(Asp433Asn), p.(Asp491Asn), p.(Asn501Tyr), p.(Ala504Val), p.(Arg523His), and p.(Leu563Arg)] in 29 patients. In vitro study of the p.(Gly36Asp), p.(Asn249Ser), p.(Ala287Val), p.(Asn501Tyr), p.(Pro562Arg) and p.(Leu563Arg) variants, however, revealed that both LPL mass and LPL activity in each of the transfected cells were not significantly different from those in the wild type LMF1 transfected cells, suggesting that these variants might not play a significant role in severe HTG phenotype in our subjects.

Highlights

Severe hypertriglyceridemia (HTG) occurs when there is massive accumulation of triglyceride-rich lipoproteins, chylomicrons and/or very low-density lipoproteins, in the bloodstream
We examined the genetic variants of the Lipase maturation factor 1 (LMF1) gene in 101 Thai subjects with severe HTG using a resequencing approach and determined their functional significance in vitro
We further identified 14 variants in the LMF1 gene, all of which were missense variants, in 29 subjects

Summary

Introduction

Severe hypertriglyceridemia (HTG) occurs when there is massive accumulation of triglyceride-rich lipoproteins, chylomicrons and/or very low-density lipoproteins, in the bloodstream. The monogenic form, called familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease due to the presence of biallelic pathogenic variants in several genes involved in triglyceride lipolysis. These candidate genes include LPL, APOC2, APOA5, GPIHBP1 and LMF1, which encode, respectively, lipoprotein lipase, apolipoprotein C2, apolipoprotein A5, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, and lipase maturation factor 1 [2,5]. The multifactorial form of chylomicronemia, called multifactorial chylomicronemia (MCM) or multifactorial chylomicronemia syndrome (MCS), is an oligogenic or polygenic disorder due to heterozygous “smaller effect” variants in candidate genes along with predisposing environmental factors [1,2,3,4,6]. While FCS is associated with a high risk of acute pancreatitis, MCM or MCS is associated with a lower risk of acute pancreatitis but a higher risk of cardiovascular disease [4,7]

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