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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1866.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding

B. Dorfmeister; W.W. Zeng; A. Dichlberger; S.K. Nilsson; F.G. Schaap; J.A. Hubacek; M. Merkel; J.A. Cooper; A. Lookene; W. Putt; R. Whittall; P.J. Lee; L. Lins; N. Delsaux; M. Nierman; J.A. Kuivenhoven; J.J.P. Kastelein; M. Vrablik; G. Olivecrona; W.J. Schneider; J. Heeren; S.E. Humphries; P.J. Talmud

From the Division of Cardiovascular Genetics, Department of Medicine (B.D., W.W.Z., J.A.C., W.P., R.W., S.E.H., P.J.T.), UCL, London, UK; the Department of Medical Biochemistry (A.D., W.J.S.), Max F. Perutz Laboratories, Medical University Vienna, Austria; the Department of Medical Biosciences/Physiological Chemistry (S.K.N., A.L., G.O.), Umeå University, Sweden; AMC Liver Center (F.G.S., M.N., J.A.K., J.J.P.K.), Amsterdam, The Netherlands; the Institute for Clinical and Experimental Medicine (J.A.H.), Prague, Czech Republic; the Department of Internal Medicine I (M.M.), University Hospital Hamburg-Eppendorf, Hamburg, Germany; the National Hospital for Neurology & Neurosurgery (P.J.L.), London, UK; the Centre de Biophysique Moléculaire Numérique (L.L.), Gembloux, Belgium; BIOSIRIS (N.D.), Crealys Park, Gembloux, Belgium; the 3rd Department of Medicine, 1st Faculty of Medicine (M.V.), Charles University, Prague, Czech Republic; the Institute for Biochemistry and Molecular Biology II (J.H.), University Hospital Hamburg-Eppendorf, Hamburg, Germany; and the Department of Chemistry (A.L.), Tallinn University of Technology, Estonia.

Correspondence to Professor Philippa Talmud, Division of Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK. E-mail p.talmud{at}ucl.ac.uk

Objective— The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible.

Methods and Results— We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (–25% [P=0.005], –36% [P<0.0001], and –23% [P=0.02]), respectively). ApoAV-C271, -X139, -X148, and 139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant.

Conclusion— The in vitro determined function of these apoAV variants only partly explains the high TG levels seen in carriers. Their occurrence in the homozygous state, coinheritance of LPL variants or common APOA5 TG-raising variant in trans, appears to be essential for their phenotypic expression.

Sequencing APOA5 in 130 severe hypertriglyceridemic patients identified 3 novel heterozygous mutations E255G, G271C, and H321L. Together with the previously reported G185C, Q139X, Q148X, and novel 139 to 147 their impact in vitro, on LPL activity and receptor binding (LR8 and LRP1), was studied.

Key Words: apolipoprotein AV • LDL-R family • LR8 • LRP1 • HSPG-bound LPL

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