Novel pathogenic variant combination in LPL causing familial chylomicronemia syndrome in an Asian family and experimental validation in vitro: a case report

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  Figure 1. Lipoprotein lipase catalyzes the hydrolysis of triglycerides. Lipoprotein lipase is synthesized in adipocytes, skeletal muscle cells and cardiac myocytes. After dimerization and activation with the help of lipase maturation factor 1 (LMF1), lipoprotein lipase is released extracellularly and binds to glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) expressed on capillary endothelial cells, which shuttles lipoprotein lipase into the capillary lumen. There, lipoprotein lipase catalyzes the hydrolysis of triglycerides, with the help of two regulators: apolipoprotein C-II and apolipoprotein A-V. ApoC-II serves as a cofactor for lipoprotein lipase, and apoA-V affects plasma triglyceride levels possibly by stabilizing the lipolytic machinery via binding to lipoproteins, endothelial proteoglycans, and lipoprotein lipase. Figure is created with BioRender.

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  Figure 2. Characterization of an Asian family of familial chylomicronemia syndrome caused by compound heterozygous variants in LPL. (A) The triglyceride levels in the patient. (B) Pedigree presentation of the studied family. The LPL p.H154R variant was colored in black while the LPL p.L263Q variant was colored in grey. Arrow indicated the patient. The triglyceride levels were labelled below the corresponding individuals. TG: triglyceride. (C) Sequencing analysis of the LPL gene showing the p.H154R variant in patient and father, and the p.L263Q variant in patient and mother. Amino acid abbreviations: V, valine; H, histidine; R, arginine; L, leucine; Q, glutamine. Nucleotide abbreviations: G, guanine; T, thymine; C, cytosine; A, adenine. (D) Visualization of the p.H154R and p.L263Q variants in the lipoprotein lipase protein structure using pymol. The residues were colored according to the following color scheme: acidic residue: red; basic residue: marine; nonpolar: orange; polar: green; cysteine: yellow. In the mutant site, both the original and mutant residues were shown. (E) Homologous protein alignment using MutationTaster2 showing the conservation of His-154 and Leu-263 residues among…

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  Figure 3. Functional validation of the LPL pathogenic variants in vitro. (A) Quantification of the expression levels of wild-type and mutant lipoprotein lipase proteins using ELISA. The LPL p.H154R variant resulted in reduced level of lipoprotein lipase whereas the LPL p.L263Q variant did not alter lipoprotein lipase level when compared to wild type (WT) control. (B) Comparison of the lipolytic activity of wild-type and mutant lipoprotein lipase proteins. One-way ANOVA, *, P<0.05; ns, non-significant. LPL, lipoprotein lipase; AU, arbitrary unit; ANOVA, analysis of variance.