title: A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production.
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.
authors.affiliation: Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
authors.forename: Pimjai
authors.initials: P
authors.lastname: Anthanont
authors.affiliation: Boston Heart Diagnostics, Framingham, MA 01702, USA.
authors.forename: Eliana
authors.initials: E
authors.lastname: Polisecki
authors.affiliation: 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.
authors.forename: Bela F
authors.initials: BF
authors.lastname: Asztalos
authors.affiliation: Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Diffenderfer
authors.affiliation: Metabolic Research Center, School of Medicine & Pharmacology and Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, Australia.
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.affiliation: Department of Medicine, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Billheimer
authors.affiliation: Department of Medicine, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Cuchel
authors.affiliation: Department of Medicine, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: 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.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
mesh_terms: D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood*; D018389:Codon, Nonsense; D003327:Coronary Disease / Q000097:blood*; D003903:Deuterium; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000378:metabolism; D017270:Lipoprotein(a) / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010375:Pedigree
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D018389:Codon, Nonsense; D017270:Lipoprotein(a); D003903:Deuterium; D007930:Leucine
keywords: Apolipoprotein kinetics; Cellular cholesterol efflux; Genetic mutation; HDL subpopulations