Document Detail

Patients with apoE3 deficiency (E2/2, E3/2, and E4/2) who manifest with hyperlipidemia have increased frequency of an Asn 291-->Ser mutation in the human LPL gene.
MedLine Citation:
PMID:  7583546     Owner:  NLM     Status:  MEDLINE    
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 291-->Ser) 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%; P < or = 7.4 x 10(-5)) and 6 of 22 hyperlipidemic E2 heterozygous patients with the apoE3/2 and E4/2 genotype (allele frequency = 13.6%; P = 2.2 x 10(-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 291-->Ser 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 291-->Ser 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.
H Zhang; P W Reymer; M S Liu; I J Forsythe; B E Groenemeyer; J Frohlich; J D Brunzell; J J Kastelein; M R Hayden; Y Ma
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  15     ISSN:  1079-5642     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  1995 Oct 
Date Detail:
Created Date:  1995-11-27     Completed Date:  1995-11-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1695-703     Citation Subset:  IM    
Department of Medicine, Academic Medical Center, Amsterdam, The Netherlands.
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MeSH Terms
Apolipoprotein E3
Apolipoproteins E / deficiency*
Base Sequence
Gene Transfer Techniques
Hyperlipidemias / genetics*,  metabolism*
Lipoprotein Lipase / genetics*,  metabolism
Middle Aged
Molecular Sequence Data
Mutagenesis, Site-Directed
Point Mutation
Grant Support
Reg. No./Substance:
0/Apolipoprotein E3; 0/Apolipoproteins E; EC Lipase

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