A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production

P. Anthanont, E.Y. Polisecki, B.F. Asztalos, M.R. Diffenderfer, Hugh Barrett, J.S. Millar, J.T. Billheimer, M. Cuchel, D.J. Rader, E.J. Schaefer

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    Abstract

    © 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.
    Original languageEnglish
    Pages (from-to)470-476
    JournalAtherosclerosis
    Volume235
    Issue number2
    DOIs
    Publication statusPublished - 2014

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    Apolipoproteins A
    Apolipoprotein A-I
    Cholesterol
    HDL Cholesterol
    Arcus Senilis
    Nonsense Codon
    Apolipoproteins B
    Ireland
    Leucine
    Isotopes
    Gas Chromatography-Mass Spectrometry
    Coronary Disease
    Macrophages
    Mutation

    Cite this

    Anthanont, P., Polisecki, E. Y., Asztalos, B. F., Diffenderfer, M. R., Barrett, H., Millar, J. S., ... Schaefer, E. J. (2014). A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production. Atherosclerosis, 235(2), 470-476. https://doi.org/10.1016/j.atherosclerosis.2014.05.935
    Anthanont, P. ; Polisecki, E.Y. ; Asztalos, B.F. ; Diffenderfer, M.R. ; Barrett, Hugh ; Millar, J.S. ; Billheimer, J.T. ; Cuchel, M. ; Rader, D.J. ; Schaefer, E.J. / A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production. In: Atherosclerosis. 2014 ; Vol. 235, No. 2. pp. 470-476.
    @article{9240bfdae8c64113a1d04ceea512f985,
    title = "A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production",
    abstract = "{\circledC} 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.",
    author = "P. Anthanont and E.Y. Polisecki and B.F. Asztalos and M.R. Diffenderfer and Hugh Barrett and J.S. Millar and J.T. Billheimer and M. Cuchel and D.J. Rader and E.J. Schaefer",
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    Anthanont, P, Polisecki, EY, Asztalos, BF, Diffenderfer, MR, Barrett, H, Millar, JS, Billheimer, JT, Cuchel, M, Rader, DJ & Schaefer, EJ 2014, 'A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production' Atherosclerosis, vol. 235, no. 2, pp. 470-476. https://doi.org/10.1016/j.atherosclerosis.2014.05.935

    A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production. / Anthanont, P.; Polisecki, E.Y.; Asztalos, B.F.; Diffenderfer, M.R.; Barrett, Hugh; Millar, J.S.; Billheimer, J.T.; Cuchel, M.; Rader, D.J.; Schaefer, E.J.

    In: Atherosclerosis, Vol. 235, No. 2, 2014, p. 470-476.

    Research output: Contribution to journalArticle

    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

    VL - 235

    SP - 470

    EP - 476

    JO - Atherosclerosis

    JF - Atherosclerosis

    SN - 0021-9150

    IS - 2

    ER -