Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia Piero Pingitore, PhD, Saverio Massimo.

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Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia Piero Pingitore, PhD, Saverio Massimo Lepore, PhD, Carlo Pirazzi, MD, PhD, Rosellina Margherita Mancina, PhD, Benedetta Maria Motta, PhD, Luca Valenti, MD, Knut Erik Berge, MD, PhD, Kjetil Retterstøl, MD, PhD, Trond P. Leren, MD, PhD, Olov Wiklund, MD, PhD, Stefano Romeo, MD, PhD Journal of Clinical Lipidology Volume 10, Issue 4, Pages 816-823 (July 2016) DOI: 10.1016/j.jacl.2016.02.015 Copyright © 2016 National Lipid Association Terms and Conditions

Figure 1 Pedigree of the families. (A) Pedigree of the family with mutation p.G256TfsX26 and (B) with mutation p.M404 R in LPL gene displaying the structure of the second-cousin consanguineous matings. Squares and circles represent male and female family members, respectively, and filled symbols denote affected individuals with homozygous mutations. Journal of Clinical Lipidology 2016 10, 816-823DOI: (10.1016/j.jacl.2016.02.015) Copyright © 2016 National Lipid Association Terms and Conditions

Figure 2 Sequence analysis of the LPL mutations. (A) Segments of genomic DNA sequences of the proband 1 and 2 showing nucleotides c.765_766, which are deleted on both alleles in the affected subjects; deleted nucleotides are shown in the red box in the sequence from the control subject. (B) Segments of genomic DNA sequences of the proband 3 showing mutated nucleotide c.1211 T > G in the red box. (Color version of figure is available online.) Journal of Clinical Lipidology 2016 10, 816-823DOI: (10.1016/j.jacl.2016.02.015) Copyright © 2016 National Lipid Association Terms and Conditions

Figure 3 In HEK293 cells transiently transfected, p.G256TfsX26 LPL mutation is less produced and not secreted, whereas p.M404 R LPL is less produced and secreted. (A) Western blotting showing levels of LPL-V5 tagged in the cell lysates of HEK293 cells transfected with wild type, p.G256TfsX26, and p.M404 R LPL; calnexin was used as loading control. (B) Western blotting showing levels of LPL-V5 tagged in the cell media of HEK293 cells transfected with wild type, p.G256TfsX26, and p.M404 R LPL; albumin was used as loading control. Journal of Clinical Lipidology 2016 10, 816-823DOI: (10.1016/j.jacl.2016.02.015) Copyright © 2016 National Lipid Association Terms and Conditions

Figure 4 LPL activity is absent in the cell media of HEK293 cells transfected with p.G256TfsX26 and p.M404 R LPL. LPL induced release of radiolabeled oleic acid from triolein was measured in cell media of HEK293 transiently transfected with wild type, p.G256TfsX26, and p.M404 R LPL. Wild type LPL medium was used as a positive control. Sodium chloride 1 M (NaCl) was used to inhibit specifically LPL activity. Journal of Clinical Lipidology 2016 10, 816-823DOI: (10.1016/j.jacl.2016.02.015) Copyright © 2016 National Lipid Association Terms and Conditions

Figure 5 LPL activity is absent in pre-heparin and post-heparin plasma from individuals with p.G256TfsX26 or p.M404 R mutations. LPL induced release of radiolabeled oleic acid from triolein was measured in pre-heparin and post-heparin plasma from subjects homozygous for the two base pair deletion frameshift mutation (p.G256TfsX26) and the missense mutation (p.M404 R). Mouse post-heparin plasma was used as a positive control for increased LPL activity in post-heparin plasma. Sodium chloride 1 M (NaCl) was used to inhibit specifically LPL activity. Pre-h: pre-heparin; Post-h: post-heparin; NaCl: sodium chloride. Journal of Clinical Lipidology 2016 10, 816-823DOI: (10.1016/j.jacl.2016.02.015) Copyright © 2016 National Lipid Association Terms and Conditions

Figure 6 Circulating LPL levels in pre-heparin and post-heparin plasma from subjects with p.G256TfsX26 or p.M404 R mutation. (A) Western blotting showing circulating levels of LPL and HTGL in pre-heparin and post-heparin plasma samples from a subject carrying the p.G256TfsX26 mutation and (B) the p.M404 R mutation. Mouse post-heparin plasma was used as a positive control (mouse and human LPL amino acidic sequences show >90% homology). Anti-human APOA1 antibody was used as a loading control. Pre-h, preheparin; Post-h, postheparin; KDa, kilodalton; LPL, lipoprotein lipase; HTGL, hepatic triglyceride lipase; APOA1, apolipoprotein A1. Journal of Clinical Lipidology 2016 10, 816-823DOI: (10.1016/j.jacl.2016.02.015) Copyright © 2016 National Lipid Association Terms and Conditions