Pimjai Anthanont1, Eliana Polisecki2, Bela F Asztalos3, Margaret R Diffenderfer1, P Hugh R Barrett4, John S Millar5, Jeffrey Billheimer6, Marina Cuchel6, Daniel J Rader6, Ernst J Schaefer7. 1. Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. 2. Boston Heart Diagnostics, Framingham, MA 01702, USA. 3. Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA; Boston Heart Diagnostics, Framingham, MA 01702, USA. 4. Metabolic Research Center, School of Medicine & Pharmacology and Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, Australia. 5. Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 6. Department of Medicine, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 7. Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA; Boston Heart Diagnostics, Framingham, MA 01702, USA. Electronic address: ernst.schaefer@tufts.edu.
Abstract
OBJECTIVE: We report a novel apolipoprotein (apo) A-I truncation (apoA-IMytilene) due to a heterozygous nonsense mutation (c.718C > T, p.Gln216*) in a 68-year-old male proband with premature coronary heart disease (CHD), corneal arcus, and very low plasma concentrations of HDL cholesterol (HDL-C) and apoA-I. Two family members also had the same mutation. Our objectives were to characterize the kindred and to examine the kinetics of apoA-I, as well as cellular cholesterol efflux capacity in the proband. METHODS: We carried out the kinetic studies using a primed constant infusion of [5,5,5-D3]L-leucine and isotopic enrichment was determined by gas chromatography mass spectrometry in the proband and seven controls with low HDL-C. To assess cellular cholesterol efflux capacity, we used a validated ex vivo system that involved incubation of J774 macrophages with apoB-depleted serum from the proband, five controls with normal HDL-C, and two controls with low HDL-C. RESULTS: Stable isotope kinetic studies indicated that the proband had an apoA-I production rate (PR) that was 41% lower than the mean PR observed in low HDL-C controls (n = 7). The cellular cholesterol efflux capacity assessment showed normalized cholesterol efflux capacity in the proband was decreased by 36% compared to the mean normalized cholesterol efflux capacity of normal controls (n = 5). CONCLUSIONS: Our data indicate that this novel heterozygous apoA-I truncation is associated with markedly decreased levels of HDL-C, plasma apoA-I, and apoA-I in large α-1 HDL particles, as well as decreased total cellular cholesterol efflux and decreased apoA-I production.
OBJECTIVE: We report a novel apolipoprotein (apo) A-I truncation (apoA-IMytilene) due to a heterozygous nonsense mutation (c.718C > T, p.Gln216*) in a 68-year-old male proband with premature coronary heart disease (CHD), corneal arcus, and very low plasma concentrations of HDL cholesterol (HDL-C) and apoA-I. Two family members also had the same mutation. Our objectives were to characterize the kindred and to examine the kinetics of apoA-I, as well as cellular cholesterol efflux capacity in the proband. METHODS: We carried out the kinetic studies using a primed constant infusion of [5,5,5-D3]L-leucine and isotopic enrichment was determined by gas chromatography mass spectrometry in the proband and seven controls with low HDL-C. To assess cellular cholesterol efflux capacity, we used a validated ex vivo system that involved incubation of J774 macrophages with apoB-depleted serum from the proband, five controls with normal HDL-C, and two controls with low HDL-C. RESULTS: Stable isotope kinetic studies indicated that the proband had an apoA-I production rate (PR) that was 41% lower than the mean PR observed in low HDL-C controls (n = 7). The cellular cholesterol efflux capacity assessment showed normalized cholesterol efflux capacity in the proband was decreased by 36% compared to the mean normalized cholesterol efflux capacity of normal controls (n = 5). CONCLUSIONS: Our data indicate that this novel heterozygous apoA-I truncation is associated with markedly decreased levels of HDL-C, plasma apoA-I, and apoA-I in large α-1 HDL particles, as well as decreased total cellular cholesterol efflux and decreased apoA-I production.
Authors: Ernst J Schaefer; Pimjai Anthanont; Margaret R Diffenderfer; Eliana Polisecki; Bela F Asztalos Journal: Prog Cardiovasc Dis Date: 2016-08-24 Impact factor: 8.194
Authors: Andrew S Geller; Eliana Y Polisecki; Margaret R Diffenderfer; Bela F Asztalos; Sotirios K Karathanasis; Robert A Hegele; Ernst J Schaefer Journal: J Lipid Res Date: 2018-10-17 Impact factor: 5.922