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J. Biol. Chem., Vol. 280, Issue 22, 21052-21060, June 3, 2005

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Mutation in Apolipoprotein B Associated with Hypobetalipoproteinemia Despite Decreased Binding to the Low Density Lipoprotein Receptor^*

Marianne Benn, Børge G. Nordestgaard¶, Jan Skov Jensen¶, Karin Nilausen||, Hans Meinertz**, and Anne Tybjærg-Hansen¶

From the Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, the Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej, DK-2730 Herlev, ^¶The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen, the ^||Department of Medical Anatomy, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen,, and the ^**Department of Medicine B, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

Mutations in apolipoprotein B (APOB) may reduce binding of low density lipoprotein (LDL) to the LDL receptor and cause hypercholesterolemia. We showed that heterozygotes for a new mutation in APOB have hypobetalipoproteinemia, despite a reduced binding of LDL to the LDL receptor. APOB R3480P heterozygotes were identified among 9,255 individuals from the general population and had reduced levels of apoB-containing lipoproteins. Most surprisingly, R3480P LDL bound with lower affinity to the LDL receptor than non-carrier LDL in vitro, and these results were confirmed by turnover studies of LDL in vivo. In very low density lipoprotein (VLDL) turnover studies, the amount of VLDL converted to LDL in R3480P heterozygotes was substantially reduced, suggesting that this was the explanation for the hypobetalipoproteinemia observed in these individuals. Our findings emphasized the importance of combining in vitro studies with both human in vivo and population-based studies, as in vitro studies often have focused on very limited aspects of complex mechanisms taken out of their natural context.

Received for publication, December 9, 2004 , and in revised form, March 4, 2005.

^* The Danish Heart Foundation, The Danish Medical Research Council, and Chief Physician Johan Boserup and Lise Boserup's Fund supported this study. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Clinical Biochemistry, KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. Tel.: 45-35454159; Fax: 45-35454160; E-mail: at-h{at}rh.dk.

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				M. Benn, M. C. A. Stene, B. G. Nordestgaard, G. B. Jensen, R. Steffensen, and A. Tybjaerg-Hansen Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of Low-Density Lipoprotein Cholesterol in the General Population J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 1038 - 1045. [Abstract] [Full Text] [PDF]

				M. Benn, B. G. Nordestgaard, J. S. Jensen, and A. Tybjaerg-Hansen Polymorphisms in Apolipoprotein B and Risk of Ischemic Stroke J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3611 - 3617. [Abstract] [Full Text] [PDF]

				M. Benn, B. G. Nordestgaard, J. S. Jensen, P. Grande, H. Sillesen, and A. Tybjaerg-Hansen Polymorphism in APOB Associated with Increased Low-Density Lipoprotein Levels in Both Genders in the General Population J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5797 - 5803. [Abstract] [Full Text] [PDF]