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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1695-1703.)
© 1995 American Heart Association, Inc.

Articles

Patients With ApoE3 Deficiency (E2/2, E3/2, and E4/2) Who Manifest With Hyperlipidemia Have Increased Frequency of an Asn 291Ser Mutation in the Human LPL Gene

Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993, and published in abstract form (Circulation. 1993;88[suppl I]:I-179).

Hanfang Zhang; Paul W. A. Reymer; Ming-Sun Liu; Ian J. Forsythe; Bjorn E. Groenemeyer; Jiri Frohlich; John D. Brunzell; John J. P. Kastelein; Michael R. Hayden; Yuanhong Ma

From the Department of Medicine (H.Z., Y.M.), the Department of Medical Genetics (H.Z., M.-S.L., I.J.F., M.R.H), and the Academic Medical Center, Amsterdam, The Netherlands (P.W.A.R, B.E.G, J.J.P.K.); the Department of Pathology (J.F.), University of British Columbia, Vancouver, Canada; and the Department of Medicine, University of Washington, Seattle (J.D.B.).

Correspondence to Dr Yuanhong Ma, Department of Medicine, Rm 416-2125 East Mall, NCE Bldg, Vancouver, BC V6T 1Z4, Canada.

Abstract Approximately 1% to 2% of persons in the general population are homozygous for a lipoprotein receptor–binding defective form of apoE (apoE2/2). However, only a small percentage (2% to 5%) of all apoE2/2 homozygotes develop type III hyperlipoproteinemia. Interaction with other genetic and environmental factors are required for the expression of this lipid abnormality. We sought to investigate the possible role of LPL gene mutations in the development of hyperlipoproteinemia in apoE2/2 homozygotes and in apoE2 heterozygotes. As a first step, we performed DNA sequence analysis of all 10 LPL coding exons in 2 patients with the apoE2/2 genotype who had type III hyperlipoproteinemia and identified a single missense mutation (Asn 291Ser) in exon 6 of the LPL gene. The mutation was then found in 5 of 18 patients with type III hyperlipoproteinemia who had the apoE2/2 genotype (allele frequency=13.9%; P7.4x10^-5) and 6 of 22 hyperlipidemic E2 heterozygous patients with the apoE3/2 and E4/2 genotype (allele frequency=13.6%; P=2.2x10^-5). In contrast, this mutation was found in only 3 of 230 normolipidemic controls (allele frequency=0.7%). In vitro mutagenesis studies revealed that the Asn 291Ser mutant LPL had approximately 60% of LPL catalytic activity and approximately 70% of specific activity compared with wild-type LPL. The heparin-binding affinity of the mutant LPL was not impaired. Our data suggest that the Asn 291Ser substitution is likely to be a significant predisposing factor contributing to the expression of different forms of hyperlipidemia when associated with other genetic factors such as the presence of apoE2.

Key Words: hyperlipoproteinemia • lipoprotein lipase • missense mutations • apoE • gene-gene interaction

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