TY - JOUR
T1 - A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production
AU - Anthanont, P.
AU - Polisecki, E.Y.
AU - Asztalos, B.F.
AU - Diffenderfer, M.R.
AU - Barrett, Hugh
AU - Millar, J.S.
AU - Billheimer, J.T.
AU - Cuchel, M.
AU - Rader, D.J.
AU - Schaefer, E.J.
PY - 2014
Y1 - 2014
N2 - © 2014 Published by Elsevier Ireland Ltd. 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 exvivo 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.
AB - © 2014 Published by Elsevier Ireland Ltd. 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 exvivo 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.
U2 - 10.1016/j.atherosclerosis.2014.05.935
DO - 10.1016/j.atherosclerosis.2014.05.935
M3 - Article
C2 - 24950002
SN - 0021-9150
VL - 235
SP - 470
EP - 476
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -