© 1997 American Heart Association, Inc.
Articles |
The Apolipoprotein E2(Arg145Cys) Mutation Causes Autosomal Dominant Type III Hyperlipoproteinemia With Incomplete Penetrance
From the MRC/UCT Research Unit for the Cell Biology of Atherosclerosis, Department of Medical Biochemistry (W.J.S. de V., D.R. van der W., G.A.C.), and the Department of Chemical Pathology and Medicine (H.E.H., A.D.M.), University of Cape Town Medical School, Cape Town, South Africa.
Correspondence to Dr A. David Marais, Department of Medicine, University of Cape Town Medical School, Observatory 7925, South Africa. E-mail dmarais{at}uctgsh1.uct.ac.za
Abstract Type III hyperlipoproteinemia (type III HLP) is an atherogenic disorder of lipoprotein metabolism characterized by the accumulation of cholesterol-enriched VLDL and is usually associated with homozygosity for a normal variant of apoE, apoE2. ApoE2(Arg145Cys) is a rare variant arising from a C
T transition at nucleotide 4031 and has been linked to type III HLP. Ten subjects from a group of 42 unrelated individuals with proven type III HLP were found to be either heterozygous or homozygous for the apoE2(Arg145Cys) mutation by DNA sequencing. The apoE4-Philadelphia (Glu13Lys, Arg145Cys) variant was subsequently excluded. None of 4 homozygotes (3 blacks and 1 of mixed ancestry) developed ischemic heart disease, but they did present with xanthomata. In contrast, 6 heterozygous subjects presented mainly with ischemic heart disease but generally lacked physical signs. Cholesterol concentrations ranged from 6.2 mmol/L to 13.3 mmol/L and triglyceride levels from 3.2 to 13.2 mmol/L. The dyslipoproteinemia in homozygous and heterozygous subjects was indistinguishable. Family investigation identified an additional 10 heterozygous mutant-allele carriers, of whom 3 had type III HLP. This unique cohort of patients indicates that the apoE2(Arg145Cys) mutation is relatively common in several population groups in our region and may be particularly prevalent in blacks. There was no clear allele dosage effect present for the development of dyslipoproteinemia or atherosclerosis. The mode of inheritance is for the first time clearly established to be autosomal dominant with incomplete penetrance.
Key Words: type III hyperlipoproteinemia • autosomal dominant inheritance • apoE2(Arg145Cys) mutation • apolipoprotein E • dysbetalipoproteinemia
This article has been cited by other articles:
 |
|
 |
|
  K. E. Kypreos and V. I. Zannis LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice J. Lipid Res., March 1, 2006; 47(3): 521 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ruiz, D. Kouiavskaia, M. Migliorini, S. Robinson, E. L. Saenko, N. Gorlatova, D. Li, D. Lawrence, B. T. Hyman, K. H. Weisgraber, et al. The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor J. Lipid Res., August 1, 2005; 46(8): 1721 - 1731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Blom, P. Byrnes, S. Jones, and A. D. Marais Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia J. Lipid Res., January 1, 2003; 44(1): 212 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. HOFFMANN, H. SCHARNAGL, E. PANAGIOTOU, W. T. BANGHARD, H. WIELAND, and W. MÄRZ Diminished LDL Receptor and High Heparin Binding of Apolipoprotein E2 Sendai Associated with Lipoprotein Glomerulopathy J. Am. Soc. Nephrol., March 1, 2001; 12(3): 524 - 530. [Abstract] [Full Text]
|
|
|
|
|
|
R. W. Mahley, Y. Huang, and S. C. Rall , Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes J. Lipid Res., November 1, 1999; 40(11): 1933 - 1949. [Abstract] [Full Text]
|
|